4-Carboxyamino-2-substituted-1,2,3,4-tetrahydroquinolines

ABSTRACT

Cholesteryl ester transfer protein inhibitors, pharmaceutical compositions containing such inhibitors and the use of such inhibitors to elevate certain plasma lipid levels, including high density lipoprotein-cholesterol and to lower certain other plasma lipid levels, such as LDL-cholesterol and triglycerides and accordingly to treat diseases which are exacerbated by low levels of HDL cholesterol and/or high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases in some mammals, including humans.

This application claims priority from provisional application U.S. Ser.No. 60/100,860 filed Sep. 17, 1998, the benefit of which is herebyclaimed under 37 C.F.R. §1.78(a)(3).

BACKGROUND OF INVENTION

This invention relates to cholesteryl ester transfer protein (CETP)inhibitors, pharmaceutical compositions containing such inhibitors andthe use of such inhibitors to elevate certain plasma lipid levels,including high density lipoprotein (HDL)-cholesterol and to lowercertain other plasma lipid levels, such as low density lipoprotein(LDL)-cholesterol and triglycerides and accordingly to treat diseaseswhich are affected by low levels of HDL cholesterol and/or high levelsof LDL-cholesterol and triglycerides, such as atherosclerosis andcardiovascular diseases in certain mammals (i.e., those which have CETPin their plasma), including humans.

Atherosclerosis and its associated coronary artery disease (CAD) is theleading cause of mortality in the industrialized world. Despite attemptsto modify secondary risk factors (smoking, obesity, lack of exercise)and treatment of dyslipidemia with dietary modification and drugtherapy, coronary heart disease (CHD) remains the most common cause ofdeath in the U.S., where cardiovascular disease accounts for 44% of alldeaths, with 53% of these associated with atherosclerotic coronary heartdisease.

Risk for development of this condition has been shown to be stronglycorrelated with certain plasma lipid levels. While elevated LDL-C may bethe most recognized form of dyslipidemia, it is by no means the onlysignificant lipid associated contributor to CHD. Low HDL-C is also aknown risk factor for CHD (Gordon, D. J., et al.,: “High-densityLipoprotein Cholesterol and Cardiovascular Disease”, Circulation,(1989), 79: 8-15).

High LDL-cholesterol and triglyceride levels are positively correlated,while high levels of HDL-cholesterol are negatively correlated with therisk for developing cardiovascular diseases. Thus, dyslipidemia is not aunitary risk profile for CHD but may be comprised of one or more lipidaberrations.

Among the many factors controlling plasma levels of these diseasedependent principles, cholesteryl ester transfer protein (CETP) activityaffects all three. The role of this 70,000 dalton plasma glycoproteinfound in a number of animal species, including humans, is to transfercholesteryl ester and triglyceride between lipoprotein particles,including high density lipoproteins (HDL), low density lipoproteins(LDL), very low density lipoproteins (VLDL), and chylomicrons. The netresult of CETP activity is a lowering of HDL cholesterol and an increasein LDL cholesterol. This effect on lipoprotein profile is believed to bepro-atherogenic, especially in subjects whose lipid profile constitutesan increased risk for CHD.

No wholly satisfactory HDL-elevating therapies exist Niacin cansignificantly increase HDL, but has serious toleration issues whichreduce compliance. Fibrates and the HMG CoA reductase inhibitors raiseHDL-C only modestly (˜10-12%). As a result, there is a significant unmetmedical need for a well-tolerated agent which can significantly elevateplasma HDL levels, thereby reversing or slowing the progression ofatherosclerosis.

Thus, although there are a variety of anti-atherosclerosis therapies,there is a continuing need and a continuing search in this field of artfor alternative therapies.

EP0818448 (970624) discloses the preparation of certain 5,6,7,8substituted tetrahydroquinolines and analogs as cholesteryl estertransfer protein inhibitors.

U.S. Pat. No. 5,231,102 discloses a class of 4-substituted1,2,3,4-tetrahydroquinolines that possess an acidic group (or groupconvertible thereto in vivo) at the 2-position that are specificantagonists of N-methyl-D-aspartate (NMDA) receptors and are thereforeuseful in the treatment and/or prevention of neurodegenerativedisorders.

U.S. Pat. No. 5,288,725 discloses pyrroloquinoline bradykininantagonists.

SUMMARY OF THE INVENTION

This invention is directed to compounds of Formula I

prodrugs thereof, and pharmaceutically acceptable salts of saidcompounds and said prodrugs;

wherein R¹ is hydrogen, Y, W—X or W—Y;

wherein W is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl;

X is —O—Y, —S—Y, —N(H)Y or —N—(Y)₂;

wherein Y for each occurrence is independently Z or a fully saturated,partially unsaturated or fully unsaturated one to ten membered straightor branched carbon chain wherein the carbons, other than the connectingcarbon, may optionally be replaced with one or two heteroatoms selectedindependently from oxygen, sulfur and nitrogen and said carbon isoptionally mono-, di- or tri-substituted independently with halo, saidcarbon is optionally mono-substituted with hydroxy, said carbon isoptionally mono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono-, ordi-substituted with oxo, and said carbon chain is optionallymono-substituted with Z;

wherein Z is a partially saturated, fully saturated or fully unsaturatedthree to eight membered ring optionally having one to four heteroatomsselected independently from oxygen, sulfur and nitrogen, or a bicyclicring consisting of two fused partially saturated, fully saturated orfully unsaturated three to six membered rings, taken independently,optionally having one to four heteroatoms selected independently fromnitrogen, sulfur and oxygen;

wherein said Z substituent is optionally mono-, di- or tri-substitutedindependently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl, hydroxy,(C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines;

R² is a partially saturated, fully saturated or fully unsaturated one tosix membered straight or branched carbon chain wherein the carbons,other than the connecting carbon, may optionally be replaced with one ortwo heteroatoms selected independently from oxygen, sulfur and nitrogenwherein said carbon atoms are optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withoxo, said carbon is optionally mono-substituted with hydroxy, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo; or said R² is a partiallysaturated, fully saturated or fully unsaturated three to seven memberedring optionally having one to two heteroatoms selected independentlyfrom oxygen, sulfur and nitrogen, wherein said R² ring is optionallyattached through (C₁-C₄)alkyl;

wherein said R² ring is optionally mono-, di- or tri-substitutedindependently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl, hydroxy,(C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, oxo or (C₁-C₆)alkyloxycarbonyl;

with the proviso that R² is not methyl;

R³ is hydrogen or Q;

wherein Q is a fully saturated, partially unsaturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V;

wherein V is a partially saturated, fully saturated or fully unsaturatedthree to eight membered ring optionally having one to four heteroatomsselected independently from oxygen, sulfur and nitrogen, or a bicyclicring consisting of two fused partially saturated, fully saturated orfully unsaturated three to six membered rings, taken independently,optionally having one to four heteroatoms selected independently fromnitrogen, sulfur and oxygen;

wherein said V substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxamoyl, mono-N— or di-N,N-(C₁-C₆) alkylcarboxamoyl, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are also optionallysubstituted with from one to nine fluorines;

R⁴ is Q¹ or V;

wherein Q¹ a fully saturated, partially unsaturated or fully unsaturatedone to six membered straight or branched carbon chain wherein thecarbons, other than the connecting carbon, may optionally be replacedwith one heteroatom selected from oxygen, sulfur and nitrogen and saidcarbon is optionally mono-, di- or tri-substituted independently withhalo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono- or di-substituted with oxo, and said carbon chain is optionallymono-substituted with V¹;

wherein V¹ is is a partially saturated, fully saturated or fullyunsaturated three to six membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen;

wherein said V¹ substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N— ordi-N,N-(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituent isalso optionally substituted with from one to nine fluorines;

wherein either R³ must contain V or R¹ must contain V¹;

R⁵, R⁶, R⁷ and R⁸ are each independently hydrogen, a bond, nitro or halowherein said bond is substituted with T or a partially saturated, fullysaturated or fully unsaturated (C₁-C₁₂) straight or branched carbonchain wherein carbon may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogenwherein said carbon atoms are optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon isoptionally mono-substituted with T;

wherein T is a partially saturated, fully saturated or fully unsaturatedthree to eight membered ring optionally having one to four heteroatomsselected independently from oxygen, sulfur and nitrogen, or a bicyclicring consisting of two fused partially saturated, fully saturated orfully unsaturated three to six membered rings, taken independently,optionally having one to four heteroatoms selected independently fromnitrogen, sulfur and oxygen;

wherein said T substituent is optionally mono-, di- or tri-substitutedindependently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, hydroxy,(C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines; and

wherein R⁵ and R⁶, or R⁶ and R⁷, and/or R⁷ and R⁸ may also be takentogether and can form at least one four to eight membered ring that ispartially saturated or fully unsaturated optionally having one to threeheteroatoms independently selected from nitrogen, sulfur and oxygen;

wherein said ring or rings formed by R⁵ and R⁶, or R⁶ and R⁷, and/or R⁷and R⁸ are optionally mono-, di- or tri-substituted independently withhalo, (C₁-C₆)alkyl, (C₁-C₄)alkylsulfonyl, (C₂-C₆)alkenyl, hydroxy,(C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N— or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines;

with the proviso that when R² is carboxyl or (C₁-C₄)alkylcarboxyl, thenR¹ is not hydrogen.

A preferred group of compounds, designated the A Group, contains thosecompounds having the Formula I as shown above wherein

R² is beta;

the C₄ nitrogen is beta:

R¹ is W—X;

W is carbonyl, thiocarbonyl or —SO₂—;

X is —O—Y—, S—Y—, N(H)—Y— or —N—(Y)₂—;

Y for each occurrence is independently Z or (C₁-C₄)alkyl, said(C₁-C₄)alkyl optionally substituted with from one to nine fluorines orhydroxy, or said (C₁-C₄)alkyl optionally mono-substituted with Z;

wherein Z is a partially saturated, fully saturated or fully unsaturatedthree to six membered ring optionally having one to two heteroatomsselected independently from oxygen, sulfur and nitrogen;

wherein said Z substituent is optionally mono-, di- or tri-substitutedindependently with halo, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio,nitro, cyano, oxo, or (C₁-C₆)alkyloxycarbonyl, said (C₁-C₄)alkyl isoptionally substituted with from one to nine fluorines;

R² is a partially saturated, fully saturated or fully unsaturated one tofour membered straight or branched carbon chain wherein the carbons,other than the connecting carbon, may optionally be replaced with oneheteroatom selected independently from oxygen, sulfur and nitrogenwherein said carbon atoms are optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withoxo, said carbon is optionally mono-substituted with hydroxy, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo; or said R² is a partiallysaturated, fully saturated or fully unsaturated three to five memberedring optionally having one heteroatom selected independently fromoxygen, sulfur and nitrogen;

wherein said R² ring is optionally mono-, di- or tri-substitutedindependently with halo, hydroxy, (C₁-C₆)alkoxy or(C₁-C₆)alkoxycarbonyl;

R³ is Q-V wherein Q is (C₁-C₄)alkyl and V is a five or six memberedpartially saturated, fully saturated or fully unsaturated ringoptionally having one to three heteroatoms selected independently fromoxygen, sulfur and nitrogen;

wherein said V ring is optionally mono-, di-, tri- or tetra-substitutedindependently with halo, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, nitro,cyano or oxo wherein said (C₁-C₆)alkyl substituent optionally has fromone to nine fluorines;

R⁴ is (C₁-C₄)alkyl;

R⁶ and R⁷ are each independently H, halo, T or (C₁-C₆)alkyl, said(C₁-C₆)alkyl optionally having from one to nine fluorines or said(C₁-C₆)alkyl is optionally mono-substituted with T;

wherein T is a partially saturated, fully saturated or fully unsaturatedfive to six membered ring optionally having one to two heteroatomsselected independently from oxygen, sulfur and nitrogen;

wherein said T substituent is optionally mono-, di- or tri-substitutedindependently with halo, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, oxo, carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N—or di-N,N-(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituentoptionally has from one to nine fluorines; and

R⁵ and R⁸ are H,

and pharmaceutically acceptable salts thereof.

A group of compounds which is preferred among the A Group of compounds,designated the B Group, contains those compounds wherein

W is carbonyl;

X is O—Y wherein Y is (C₁-C₄)alkyl, said (C₁-C₄)alkyl substituentoptionally substituted with from one to nine fluorines or hydroxy;

Q is (C₁-C₄)alkyl and V is phenyl, pyridinyl, or pyrimidinyl;

wherein said V ring is optionally mono-, di- or tri-substitutedindependently with halo, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, nitro,cyano or oxo wherein said (C₁-C₆)alkyl substituent optionally has fromone to nine fluorines;

R² is a fully saturated (C₁-C₄) straight or branched carbon chain; orsaid R² is a fully saturated three to five membered ring; wherein saidR² chain or ring is optionally mono-, di- or tri-substitutedindependently with halo;

R⁶ and R⁷ are each independently hydrogen, halo or (C₁-C₆)alkyl, said(C₁-C₆)alkyl optionally having from one to nine fluorines; and

pharmaceutically acceptable salts thereof.

A group of compounds which is preferred among the B Group of compoundsdesignated the C Group, contains those compounds wherein

Q is methyl and V is phenyl or pyridinyl;

wherein said V ring is optionally mono-, di- or tri-substitutedindependently with halo, (C₁-C₂)alkyl, or nitro wherein said(C₁-C₂)alkyl optionally has from one to five fluorines, andpharmaceutically acceptable salts thereof.

Especially preferred compounds of Formula I are the compounds

[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-chloro-2-cyclopropyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[2S,4S]2-cyclopropyl-4-[(3,5-dichloro-benzyl)methoxycarbonyl-amino]-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester;

[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclobutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

and pharmaceutically acceptable salts of said compounds.

Especially preferred compounds of Formula I are the compounds

[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)methoxycarbonyl-amino]-2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid 2-hydroxy-ethyl ester;

[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester;

[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester;

and pharmaceutically acceptable salt thereof.

Especially preferred compounds within the C Group of compounds arecompounds wherein

a. Y is isopropyl;

R² is isopropyl;

R³ is 3,5-bis-trifluoromethylphenylmethyl;

R⁴ is methyl;

R⁶ is trifluoromethyl; and

R⁷is H;

b. Y is isopropyl;

R² is cyclopropyl;

R³ is 3,5-bis-trifluoromethylphenylmethyl;

R⁴ is methyl;

R⁶ is chloro; and

R⁷ is H;

c. Y is isopropyl;

R² is cyclopropyl;

R³ is 3,5-dichlorophenylmethyl;

R⁴ is methyl;

R⁶ is trifluoromethyl; and

R⁷ is H;

d. Y is tert-butyl;

R² is cyclopropyl;

R³ is 3,5-bis-trifluoromethylphenylmethyl;

R⁴ is methyl;

R⁶ trifluoromethyl; and

R⁷ is H;

e. Y is isopropyl;

R² is cyclopropyl;

R³ is 3,5-bis-trifluoromethylphenylmethyl;

R⁴ is methyl;

R⁶ trifluoromethyl; and

R⁷ is H;

f. Y is isopropyl;

R² is cyclobutyl;

R³ is 3,5bis-trifluoromethylphenylmethyl;

R⁴ is methyl;

R⁶ trifluoromethyl; and

R⁷ is H;

g. Y is isopropyl;

R² is ethyl;

R³ is 3,5-bis-trifluoromethylphenylmethyl;

R⁴ is methyl;

R⁶ is trifluoromethyl; and

R⁷ is H;

h. Y is isopropyl;

R² is methoxymethyl;

R³ is 3,5-bis-trifluoromethylphenylmethyl;

R⁴ is methyl;

R⁶ is trifluoromethyl; and

R⁷ is H;

I. Y is 2-hydroxyethyl;

R² is ethyl;

R³ is 3,5-bis-trifluoromethylphenylmethyl;

R⁴ is methyl;

R⁵ is trifluoromethyl; and

R⁷ is H;

j. Y is ethyl;

R² is cyclopropyl;

R³ is 3,5-bis-trifluoromethylphenylmethyl;

R⁴ is methyl;

R⁶ is trifluoromethyl; and

R⁷ is H;

k. Y is ethyl;

R² is ethyl;

R³ is 3,5-bis-trifluoromethylphenylmethyl;

R⁴ is methyl;

R⁶ is trifluoromethyl; and

R⁷ is H;

l. Y is n-propyl;

R² is cyclopropyl;

R³ is 3,5-bis-trifluoromethylphenylmethyl;

R⁴ is methyl;

R⁶ is trifluoromethyl; and

R⁷ is H; and

m. Y is n-propyl;

R² is ethyl;

R³ is 3,5-bis-trifluoromethylphenylmethyl;

R⁴ is methyl;

R⁶ is trifluoromethyl; and

R⁷ is H; and pharmaceutically acceptable salts of said compounds.

Other preferred compounds are the compounds

[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-chloro-2-cyclopropyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[2S,4S]2-cyclopropyl-4-[(3,5-dichloro-benzyl)-methoxycarbonyl-amino]-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester;

[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclobutyl-4-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester;

[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid 2-hydroxy-ethyl ester;

[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester;

[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicadd propyl ester;

[2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-4-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester;

and pharmaceutically acceptable salts of said compounds.

A preferred group of compounds, designated the E Group, contains thosecompounds having the Formula I as shown above wherein

R² is beta;

the C⁴ nitrogen is beta;

R¹ is W—X;

W is carbonyl, thiocarbonyl or sulfonyl;

X is —O—Y—, S—Y—, N(H)—Y— or —N—(Y)₂—;

Y for each occurrence is independently Z or (C₁-C₄)alkyl, said(C₁-C₄)alkyl optionally having from one to nine fluorines or said(C₁-C₄)alkyl optionally mono-substituted with Z;

wherein Z is a partially saturated, fully saturated or fully unsaturatedthree to six membered ring optionally having one to two heteroatomsselected independently from oxygen, sulfur and nitrogen;

wherein said Z substituent is optionally mono-, di- or tri-substitutedindependently with halo, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio,nitro, cyano, oxo, or (C₁-C₆)alkyloxycarbonyl, said (C₁-C₄)alkylsubstituent optionally substituted with from one to nine fluorines;

R² is a partially saturated, fully saturated or fully unsaturated one tofour membered straight or branched carbon chain wherein the carbons,other than the connecting carbon, may optionally be replaced with oneheteroatom selected independently from oxygen, sulfur and nitrogenwherein said carbon atoms are optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withoxo, said carbon is optionally mono-substituted with hydroxy, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo; or said R² is a partiallysaturated, fully saturated or fully unsaturated three to five memberedring optionally having one heteroatom selected independently fromoxygen, sulfur and nitrogen;

wherein said R² ring is optionally mono-, di- or tri-substitutedindependently with halo, hydroxy, (C₁-C₆)alkoxy or(C₁-C₆)alkoxycarbonyl;

R³ is Q-V wherein Q is (C₁-C₄)alkyl and V is a five or six memberedpartially saturated, fully saturated or fully unsaturated ringoptionally having one to three heteroatoms selected independently fromoxygen, sulfur and nitrogen;

wherein said V ring is optionally mono-, di-, tri- or tetra-substitutedindependently with halo, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, nitro,cyano or oxo wherein said (C₁-C₆)alkyl substituent optionally has fromone to nine fluorines;

R⁴ is (C₁-C₄)alkyl; and

R⁵ and R⁶, or R⁶ and R⁷, or R⁷ and R⁸ are taken together and form onering that is a partially saturated or fully unsaturated five or sixmembered ring optionally having one to two heteroatoms independentlyselected from nitrogen, sulfur and oxygen;

wherein said ring formed by R⁵ and R⁶, or R⁶ and R⁷, or R⁷ and R⁸ areoptionally mono-, di- or tri-substituted independently with halo,(C₁-C₄)alkyl, (C₁-C₄)alkylsulfonyl, (C₂-C₄)alkenyl, hydroxy,(C₁-C₄)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₄)alkyloxycarbonyl, mono-N— or di-N,N-(C₁-C₄)alkylamino whereinsaid (C₁-C₄)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₄)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₄)alkyloxycarbonyl, mono-N— or di-N,N-(C₁-C₄)alkylamino or said(C₁-C₄)alkyl substituent optionally has from one to nine fluorines;

provided that the R⁵, R⁶, R⁷ and/or R⁸, as the case may be, that do notform the ring are hydrogen;

and pharmaceutically acceptable salts thereof.

A preferred group of compounds, designated the F Group, contains thosecompounds having the Formula I as shown above wherein

R² is beta;

the C⁴ nitrogen is beta;

R¹ is W—Y;

W is carbonyl, thiocarbonyl or sulfonyl;

Y is (C₁-C₆)alkyl, said (C₁-C₆)alkyl optionally having from one to ninefluorines or said (C₁-C₆)alkyl optionally mono-substituted with Z;

wherein Z is a partially saturated, fully saturated or fully unsaturatedthree to six membered ring optionally having one to two heteroatomsselected independently from oxygen, sulfur and nitrogen;

wherein said Z substituent is optionally mono-, di- or tri-substitutedindependently with halo, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio,nitro, cyano, oxo, or (C₁-C₆)alkyloxycarbonyl, said (C₁-C₄)alkyloptionally substituted with from one to nine fluorines;

R² is a partially saturated, fully saturated or fully unsaturated one tofour membered straight or branched carbon chain wherein the carbons,other than the connecting carbon, may optionally be replaced with oneheteroatom selected independently from oxygen, sulfur and nitrogenwherein said carbon atoms are optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withoxo, said carbon is optionally mono-substituted with hydroxy, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo; or said R² is a partiallysaturated, fully saturated or fully unsaturated three to five memberedring optionally having one heteroatom selected independently fromoxygen, sulfur and nitrogen;

wherein said R² ring is optionally mono-, di- or tri-substitutedindependently with halo, hydroxy, (C₁-C₆)alkoxy or(C₁-C₆)alkoxycarbonyl;

R³ is Q-V wherein Q is (C₁-C₄)alkyl and V is a five or six memberedpartially saturated, fully saturated or fully unsaturated ringoptionally having one to three heteroatoms selected independently fromoxygen, sulfur and nitrogen;

wherein said V ring is optionally mono-, di-, tri- or tetra-substitutedindependently with halo, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, nitro,cyano or oxo wherein said (C₁-C₆)alkyl substituent optionally has fromone to nine fluorines;

R⁴ is (C₁-C₄)alkyl;

R⁶ and R⁷ are each independently (C₁-C₆)alkyl or (C₁-C₆)alkoxy, said(C₁-C₆)alkyl or (C₁-C₆)alkoxy substituents optionally having from one tonine fluorines or said (C₁-C₆)alkoxy or (C₁-C₆)alkyl substituentsoptionally mono-substituted with T;

wherein T is a partially saturated, fully saturated or fully unsaturatedfive to six membered ring optionally having one to two heteroatomsselected independently from oxygen, sulfur and nitrogen;

wherein said T substituent is optionally mono-, di- or tri-substitutedindependently with halo, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, oxo, carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N—or di-N,N-(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituentoptionally has from one to nine fluorines;

or R⁶ and R⁷ are taken together and form one ring that is a partiallysaturated or fully unsaturated five or six membered ring optionallyhaving one to two heteroatoms independently selected from nitrogen,sulfur and oxygen;

wherein said ring formed by R⁶ and R⁷ is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₄)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₄)alkenyl, hydroxy, (C₁-C₄)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₄)alkyloxycarbonyl, mono-N— or di-N,N-(C₁-C₄)alkylamino whereinsaid (C₁-C₄)alkyl substituent optionally has from one to nine fluorines;

R⁵ and R⁸ are H; and

pharmaceutically acceptable salts thereof.

A preferred group of compounds, designated the G Group, contains thosecompounds having the Formula I as shown above wherein

R² is beta;

the C₄ nitrogen is beta;

R¹ is Y;

Y is (C₂-C₆)alkenyl or (C₁-C₆)alkyl, said (C₂-C₆)alkenyl or (C₁-C₆)alkyloptionally having from one to nine fluorines or said (C₂-C₆)alkenyl or(C₁-C₆)alkyl optionally mono-substituted with Z;

wherein Z is a partially saturated, fully saturated or fully unsaturatedthree to six membered ring optionally having one to two heteroatomsselected independently from oxygen, sulfur and nitrogen;

wherein said Z substituent is optionally mono-, di- or tri-substitutedindependently with halo, (C₁-C₆)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio,nitro, cyano, oxo, or (C₁-C₆)alkyloxycarbonyl, said (C₁-₄)alkylsubstituent optionally substituted with from one to nine fluorines;

R² is a partially saturated, fully saturated or fully unsaturated one tofour membered straight or branched carbon chain wherein the carbons,other than the connecting carbon, may optionally be replaced with oneheteroatom selected independently from oxygen, sulfur and nitrogenwherein said carbon atoms are optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withoxo, said carbon is optionally mono-substituted with hydroxy, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo; or said R² is a partiallysaturated, fully saturated or fully unsaturated three to five memberedring optionally having one heteroatom selected independently fromoxygen, sulfur and nitrogen;

wherein said R² ring is optionally mono-, di- or tri-substitutedindependently with halo, hydroxy, (C₁-C₆)alkoxy or(C₁-C₆)alkoxycarbonyl;

R³ is Q-V wherein Q is (C₁-C₄)alkyl and V is a five or six memberedpartially saturated, fully saturated or fully unsaturated ringoptionally having one to three heteroatoms selected independently fromoxygen, sulfur and nitrogen;

wherein said V ring is optionally mono-, di-, tri- or tetra-substitutedindependently with halo, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, nitro,cyano or oxo wherein said (C₁-C₆)alkyl substituent optionally has fromone to nine fluorines;

R⁴ is (C₁-C₄)alkyl;

R⁶ and R⁷ are each independently (C₁-C₆)alkyl or (C₁-C₆)alkoxy, said(C₁-C₆)alkyl or (C₁-C₆)alkoxy substituents optionally having from one tonine fluorines or said (C₁-C₆)alkoxy or (C₁-C₆)alkyl substituentsoptionally mono-substituted with T,

wherein T is a partially saturated, fully saturated or fully unsaturatedfive to six membered ring optionally having one to two heteroatomsselected independently from oxygen, sulfur and nitrogen;

wherein said T substituent is optionally mono-, di- or tri-substitutedindependently with halo, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, oxo, carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N—or di-N,N-(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituentoptionally has from one to nine fluorines;

or R⁶ and R⁷ are taken together and form one ring that is a partiallysaturated or fully unsaturated five or six membered ring optionallyhaving one to two heteratoms independently selected from nitrogen,sulfur and oxygen;

wherein said ring formed by R⁶ and R⁷ is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₄)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₄)alkenyl, hydroxy, (C₁-C₄)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₄)alkyloxycarbonyl, mono-N— or di-N,N-(C₁-C₄)alkylamino whereinsaid (C₁-C₄)alkyl substituent optionally has from one to nine fluorines;

R⁵ and R⁸ are H; and pharmaceutically acceptable salts thereof.

A preferred group of compounds, designated the H Group, contains thosecompounds having the Formula I as shown above wherein

R² is beta;

the C₄ nitrogen is beta;

R¹ is Z;

Z is a partially saturated, fully saturated or fully unsaturated threeto six membered ring optionally having one to two heteroatoms selectedindependently from oxygen, sulfur and nitrogen;

wherein said Z substituent is optionally mono-, di- or tri-substitutedindependently with halo, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio,nitro, cyano, oxo, or (C₁-C₆)alkyloxycarbonyl, said (C₁-C₄)alkylsubstituent optionally having one to nine fluorines;

R² is a partially saturated, fully saturated or fully unsaturated one tofour membered straight or branched carbon chain wherein the carbons,other than the connecting carbon, may optionally be replaced with oneheteroatom selected independently from oxygen, sulfur and nitrogenwherein said carbon atoms are optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withoxo, said carbon is optionally mono-substituted with hydroxy, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo; or said R² is a partiallysaturated, fully saturated or fully unsaturated three to five memberedring optionally having one heteroatom selected independently fromoxygen, sulfur and nitrogen;

wherein said R² ring is optionally mono-, di- or tri-substitutedindependently with halo, hydroxy, (C₁-C₆)alkoxy or(C₁-C₆)alkoxycarbonyl;

R³ is Q-V wherein Q is (C₁-C₄)alkyl and V is a five or six memberedpartially saturated, fully saturated or fully unsaturated ringoptionally having one to three heteroatoms selected independently fromoxygen, sulfur and nitrogen;

wherein said V ring is optionally mono-, di-, tri- or tetra-substitutedindependently with halo, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, nitro,cyano or oxo wherein said (C₁-C₆)alkyl substituent optionally has fromone to nine fluorines;

R⁴ is (C₁-C₄)alkyl;

R⁶ and R⁷ are each independently (C₁-C₆)alkyl or (C₁-C₆)alkoxy, said(C₁-C₆)alkyl or (C₁-C₆)alkoxy substituents optionally having from one tonine fluorines or said (C₁-C₆)alkoxy or (C₁-C₆)alkyl substituentsoptionally mono-substituted with T;

wherein T is a partially saturated, fully saturated or fully unsaturatedfive to six membered ring optionally having one to two heteroatomsselected independently from oxygen, sulfur and nitrogen;

wherein said T substituent is optionally mono-, di- or tri-substitutedindependently with halo, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, oxo, carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N—or di-N,N-(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituentoptionally has from one to nine fluorines;

or R⁶ and R⁷ are taken together and form one ring that is a partiallysaturated or fully unsaturated five or six membered ring optionallyhaving one to two heteratoms independently selected from nitrogen,sulfur and oxygen;

wherein said ring formed by R⁶ and R⁷ is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₄)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₄)alkenyl, hydroxy, (C₁-C₄)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₄)alkyloxycarbonyl, mono-N— or di-N,N-(C₁-C₄)alkylamino whereinsaid (C₁-C₄)alkyl substituent optionally has from one to nine fluorines;

R⁵ and R⁸ are H; and pharmaceutically acceptable salts thereof.

A preferred group of compounds, designated the I Group, contains thosecompounds having the Formula I as shown above wherein

R² is beta;

the C⁴ nitrogen is beta;

R¹ is W-Z;

W is carbonyl, thiocarbonyl or sulfonyl;

Z is a partially saturated, fully saturated or fully unsaturated threeto six membered ring optionally having one to two heteroatoms selectedindependently from oxygen, sulfur and nitrogen;

wherein said Z substituent is optionally mono-, di- or tri-substitutedindependently with halo, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio,nitro, cyano, oxo, or (C₁-C₆)alkyloxycarbonyl, said (C₁-C₄)alkylsubstituent optionally having from one to nine fluorines;

R² is a partially saturated, fully saturated or fully unsaturated one tofour membered straight or branched carbon chain wherein the carbons,other than the connecting carbon, may optionally be replaced with oneheteroatom selected independently from oxygen, sulfur and nitrogenwherein said carbon atoms are optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withoxo, said carbon is optionally mono-substituted with hydroxy, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo; or said R² is a partiallysaturated, fully saturated or fully unsaturated three to five memberedring optionally having one heteroatom selected independently fromoxygen, sulfur and nitrogen;

wherein said R² ring is optionally mono-, di- or tri-substitutedindependently with halo, hydroxy, (C-C₆)alkoxy or (C₁-C₆)alkoxycarbonyl;

R³ is Q-V wherein Q is (C₁-C₄)alkyl and V is a five or six memberedpartially saturated, fully saturated or fully unsaturated ringoptionally having one to three heteroatoms selected independently fromoxygen, sulfur and nitrogen;

wherein said V ring is optionally mono-, di-, tri- or tetra-substitutedindependently with halo, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, nitro,cyano or oxo wherein said (C₁-C₆)alkyl substituent optionally has fromone to nine fluorines;

R⁴ is (C₁-C₄)alkyl;

R⁶ and R⁷ are each independently (C₁-C₆)alkyl or (C₁-C₆)alkoxy, said(C₁-C₆)alkyl or (C₁-C₆)alkoxy substituents optionally having from one tonine fluorines or said (C₁-C₆)alkoxy or (C₁-C₆)alkyl substituentsoptionally mono-substituted with T;

wherein T is a partially saturated, fully saturated or fully unsaturatedfive to six membered ring optionally having one to two heteroatomsselected independently from oxygen, sulfur and nitrogen;

wherein said T substituent is optionally mono-, di- or tri-substitutedindependently with halo, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, oxo, carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N—or di-N,N-(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituentoptionally has from one to nine fluorines;

or R⁶ and R⁷ are taken together and form one ring that is a partiallysaturated or fully unsaturated five or six membered ring optionallyhaving one to two heteroatoms independently selected from nitrogen,sulfur and oxygen;

wherein said ring formed by R⁶ and R⁷ is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₄)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₄)alkenyl, hydroxy, (C₁-C₄)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₄)alkyloxycarbonyl, mono-N— or di-N,N-(C₁-C₄)alkylamino whereinsaid (C₁-C₄)alkyl substituent optionally has from one to nine fluorines;

R⁵ and R⁸ are H; or a pharmaceutically acceptable salts thereof

A preferred group of compounds, designated the J Group, contains thosecompounds having the Formula I as shown above wherein

R² is beta;

the C⁴ nitrogen is beta;

R¹ is W—X;

W is carbonyl, thiocarbonyl or sulfonyl;

X is —O—Y—, S—Y—, N(H)—Y— or —N—(Y)₂;

Y for each occurrence is independently Z or (C₁-C₄)alkyl, said(C₁-C₄)alkyl substituent optionally having from one to nine fluorines orsaid (C₁-C₄)alkyl optionally mono-substituted with Z;

wherein Z is a partially saturated, fully saturated or fully unsaturatedthree to six membered ring optionally having one to two heteroatomsselected independently from oxygen, sulfur and nitrogen;

wherein said Z substituent is optionally mono-, di- or tri-substitutedindependently with halo, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio,nitro, cyano, oxo, or (C₁-C₆)alkyloxycarbonyl, said (C₁-C₄)alkylsubstituent optionally substituted with from one to nine fluorines;

R² is a partially saturated, fully saturated or fully unsaturated one tofour membered straight or branched carbon chain wherein the carbons,other than the connecting carbon, may optionally be replaced with oneheteroatom selected independently from oxygen, sulfur and nitrogenwherein said carbon atoms are optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withoxo, said carbon is optionally mono-substituted with hydroxy, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo; or said R² is a partiallysaturated, fully saturated or fully unsaturated three to five memberedring optionally having one heteroatom selected independently fromoxygen, sulfur and nitrogen;

wherein said R² ring is optionally mono-, di- or tri-substitutedindependently with halo, hydroxy, (C₁-C₆)alkoxy or(C₁-C₆)alkoxycarbonyl;

R³ is Q-V wherein Q is (C₁-C₄)alkyl and V is a five or six memberedpartially saturated, fully saturated or fully unsaturated ringoptionally having one to three heteroatoms selected independently fromoxygen, sulfur and nitrogen;

wherein said V ring is optionally mono-, di-, tri- or tetra-substitutedindependently with halo, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, nitro,cyano or oxo wherein said (C₁-C₆)alkyl substituent optionally has fromone to nine fluorines;

R⁴ is (C₁-C₄)alkyl;

at least one of R⁶ and R⁷ is (C₁-C₄)alkoxy and at least one of R⁵ and R⁷is (C₁-C₆)alkyl, said (C₁-C₆)alkyl and (C₁-C₄)alkoxy substituentsoptionally having from one to nine fluorines or said (C₁-C₆)alkyl and(C₁-C₄)alkoxy substituents optionally mono-substituted with T;

wherein T is a partially saturated, fully saturated or fully unsaturatedfive to six membered ring optionally having one to two heteroatomsselected independently from oxygen, sulfur and nitrogen;

wherein said T substituent is optionally mono-, di- or tri-substitutedindependently with halo, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, oxo, carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N—or di-N,N-(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituentoptionally has from one to nine fluorines;

R⁵ and R⁸ are H; and pharmaceutically acceptable salts thereof.

Yet another aspect of this invention is directed to methods for treatingatherosclerosis, peripheral vascular disease, dyslipidemia,hyperbetalipoproteinemia, hypoalphalipoproteinemia,hypercholesterolemia, hypertriglyceridemia,familial-hypercholesterolemia, cardiovascular disorders, angina,ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusioninjury, angioplastic restenosis, hypertension, vascular complications ofdiabetes, obesity or endotoxemia in a mammal (including a human beingeither male or female) by administering to a mammal in need of suchtreatment an atherosclerosis, peripheral vascular disease, dyslipidemia,hyperbetalipoproteinemia, hypoalphalipoproteinemia,hypercholesterolemia, hypertriglyceridemia,familial-hypercholesterolemia, cardiovascular disorders, angina,ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusioninjury, angioplastic restenosis, hypertension, vascular complications ofdiabetes, obesity or endotoxemia treating amount of a Formula Icompound, a prodrug thereof, or a pharmaceutically acceptable salt ofsaid compound or of said prodrug.

Yet another aspect of this invention is directed to a method fortreating atherosclerosis in a mammal (including a human being) byadministering to a mammal in need of such treatment an atherosclerotictreating amount of a Formula I compound, a prodrug thereof, or apharmaceutically acceptable salt of said compound or of said prodrug.

Yet another aspect of this invention is directed to a method fortreating peripheral vascular disease in a mammal (including a humanbeing) by administering to a mammal in need of such treatment aperipheral vascular disease treating amount of a Formula I compound, aprodrug thereof, or a pharmaceutically acceptable salt of said compoundor of said prodrug.

Yet another aspect of this invention is directed to a method fortreating dyslipidemia in a mammal (including a human being) byadministering to a mammal in need of such treatment a dyslipidemiatreating amount of a Formula I compound, a prodrug thereof, or apharmaceutically acceptable salt of said compound or of said prodrug.

Yet another aspect of this invention is directed to a method fortreating hyperbetalipoproteinemia in a mammal (including a human being)by administering to a mammal in need of such treatment ahyperbetalipoproteinemia treating amount of a Formula I compound, aprodrug thereof, or a pharmaceutically acceptable salt of said compoundor of said prodrug.

Yet another aspect of this invention is directed to a method fortreating hypoalphalipoproteinemia in a mammal (including a human being)by administering to a mammal in need of such treatment ahypoalphalipoproteinemia treating amount of a Formula I compound, aprodrug thereof, or a pharmaceutically acceptable salt of said compoundor of said prodrug.

Yet another aspect of this invention is directed to a method fortreating hypercholesterolemia in a mammal (including a human being) byadministering to a mammal in need of such treatment ahypercholesterolemia treating amount of a Formula I compound, a prodrugthereof, or a pharmaceutically acceptable salt of said compound or ofsaid prodrug.

Yet another aspect of this invention is directed to a method fortreating hypertriglyceridemia in a mammal (including a human being) byadministering to a mammal in need of such treatment ahypertriglyceridemia treating amount of a Formula I compound, a prodrugthereof, or a pharmaceutically acceptable salt of said compound or ofsaid prodrug.

Yet another aspect of this invention is directed to a method fortreating familial-hypercholesterolemia in a mammal (including a humanbeing) by administering to a mammal in need of such treatment afamilial-hypercholesterolemia treating amount of a Formula I compound, aprodrug thereof, or a pharmaceutically acceptable salt of said compoundor of said prodrug.

Yet another aspect of this invention is directed to a method fortreating cardiovascular disorders in a mammal (including a human being)by administering to a mammal in need of such treatment a cardiovasculardisorder treating amount of a Formula I compound, a prodrug thereof, ora pharmaceutically acceptable salt of said compound or of said prodrug.

Yet another aspect of this invention is directed to a method fortreating angina in a mammal (including a human being) by administeringto a mammal in need of such treatment an angina treating amount of aFormula I compound, a prodrug thereof, or a pharmaceutically acceptablesalt of said compound or of said prodrug.

Yet another aspect of this invention is directed to a method fortreating ischemia in a mammal (including a human being) by administeringto a mammal in need of such treatment an ischemic disease treatingamount of a Formula I compound, a prodrug thereof, or a pharmaceuticallyacceptable salt of said compound or of said prodrug.

Yet another aspect of this invention is directed to a method fortreating cardiac ischemia in a mammal (including a human being) byadministering to a mammal in need of such treatment a cardiac ischemictreating amount of a Formula I compound, a prodrug thereof, or apharmaceutically acceptable salt of said compound or of said prodrug.

Yet another aspect of this invention is directed to a method fortreating stroke in a mammal (including a human being) by administeringto a mammal in need of such treatment a stroke treating amount of aFormula I compound, a prodrug thereof, or a pharmaceutically acceptablesalt of said compound or of said prodrug.

Yet another aspect of this invention is directed to a method fortreating a myocardial infarction in a mammal (including a human being)by administering to a mammal in need of such treatment a myocardialinfarction treating amount of a Formula I compound, a prodrug thereof,or a pharmaceutically acceptable salt of said compound or of saidprodrug.

Yet another aspect of this invention is directed to a method fortreating reperfusion injury in a mammal (including a human being) byadministering to a mammal in need of such treatment a reperfusion injurytreating amount of a Formula I compound, a prodrug thereof, or apharmaceutically acceptable salt of said compound or of said prodrug.

Yet another aspect of this invention is directed to a method fortreating angioplastic restenosis in a mammal (including a human being)by administering to a mammal in need of such treatment an angioplasticrestenosis treating amount of a Formula I compound, a prodrug thereof,or a pharmaceutically acceptable salt of said compound or of saidprodrug.

Yet another aspect of this invention is directed to a method fortreating hypertension in a mammal (including a human being) byadministering to a mammal in need of such treatment a hypertensiontreating amount of a Formula I compound, a prodrug thereof, or apharmaceutically acceptable salt of said compound or of said prodrug.

Yet another aspect of this invention is directed to a method fortreating the vascular complications of diabetes in a mammal (including ahuman being) by administering to a mammal in need of such treatment avascular complications of diabetes treating amount of a Formula Icompound, a prodrug thereof, or a pharmaceutically acceptable salt ofsaid compound or of said prodrug.

Yet another aspect of this invention is directed to a method fortreating obesity in a mammal (including a human being) by administeringto a mammal in need of such treatment an obesity treating amount of aFormula I compound, a prodrug thereof, or a pharmaceutically acceptablesalt of said compound or of said prodrug.

Yet another aspect of this invention is directed to a method fortreating endotoxemia in a mammal (including a human being) byadministering to a mammal in need of such treatment an endotoxemiatreating amount of a Formula I compound, a prodrug thereof, or apharmaceutically acceptable salt of said compound or of said prodrug.

A preferred dosage is about 0.001 to 100 mg/kg/day of a Formula Icompound, a prodrug thereof, or a pharmaceutically acceptable salt ofsaid compound or of said prodrug. An especially preferred dosage isabout 0.01 to 10 mg/kg/day of a Formula I compound, a prodrug thereof,or a pharmaceutically acceptable salt of said compound or of saidprodrug.

This invention is also directed to pharmaceutical compositions whichcomprise a therapeutically effective amount of a compound of Formula I,a prodrug thereof, or a pharmaceutically acceptable salt of saidcompound or of said prodrug and a pharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for thetreatment of atherosclerosis, peripheral vascular disease, dyslipidemia,hyperbetalipoproteinemia, hypoalphalipoproteinemia,hypercholesterolemia, hypertriglyceridemia,familial-hypercholesterolemia, cardiovascular disorders, angina,ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusioninjury, angioplastic restenosis, hypertension, vascular complications ofdiabetes, obesity or endotoxemia in a mammal (including a human being)which comprise a therapeutically effective amount of a compound ofFormula I, a prodrug thereof, or a pharmaceutically acceptable salt ofsaid compound or of said prodrug and a pharmaceutically acceptablecarrier.

This invention is also directed to pharmaceutical compositions for thetreatment of atherosclerosis in a mammal (including a human being) whichcomprise an atherosclerosis treating amount of a compound of Formula I,a prodrug thereof, or a pharmaceutically acceptable salt of saidcompound or of said prodrug and a pharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for thetreatment of peripheral vascular disease in a mammal (including a humanbeing) which comprise a peripheral vascular disease treating amount of acompound of Formula I, a prodrug thereof, or a pharmaceuticallyacceptable salt of said compound or of said prodrug and apharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for thetreatment of dyslipidemia in a mammal (including a human being) whichcomprise a dyslipidemia treating amount of a compound of Formula I, aprodrug thereof, or a pharmaceutically acceptable salt of said compoundor of said prodrug and a pharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for thetreatment of hyperbetalipoproteinemia in a mammal (including a humanbeing) which comprise a hyperbetalipoproteinemia treating amount of acompound of Formula I, a prodrug thereof, or a pharmaceuticallyacceptable salt of said compound or of said prodrug and apharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for thetreatment of hypoalphalipoproteinemia in a mammal (including a humanbeing) which comprise a hypoalphalipoproteinemia treating amount of acompound of Formula I, a prodrug thereof, or a pharmaceuticallyacceptable salt of said compound or of said prodrug and apharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for thetreatment of hypercholesterolemia in a mammal (including a human being)which comprise a hypercholesterolemia treating amount of a compound ofFormula I, a prodrug thereof, or a pharmaceutically acceptable salt ofsaid compound or of said prodrug and a pharmaceutically acceptablecarrier.

This invention is also directed to pharmaceutical compositions for thetreatment of hypertriglyceridemia in a mammal (including a human being)which comprise a hypertriglyceridemia treating amount of a compound ofFormula I, a prodrug thereof, or a pharmaceutically acceptable salt ofsaid compound or of said prodrug and a pharmaceutically acceptablecarrier.

This invention is also directed to pharmaceutical compositions for thetreatment of familial-hypercholesterolemia in a mammal (including ahuman being) which comprise a familial-hypercholesterolemia treatingamount of a compound of Formula I, a prodrug thereof, or apharmaceutically acceptable salt of said compound or of said prodrug anda pharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for thetreatment of angina in a mammal (including a human being) which comprisean angina treating amount of a compound of Formula I, a prodrug thereof,or a pharmaceutically acceptable salt of said compound or of saidprodrug and a pharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for thetreatment of ischemia in a mammal (including a human being) whichcomprise an ischemic treating amount of a compound of Formula I, aprodrug thereof, or a pharmaceutically acceptable salt of said compoundor of said prodrug and a pharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for thetreatment of cardiac ischemia in a mammal (including a human being)which comprise a cardiac ischemic treating amount of a compound ofFormula I, a prodrug thereof, or a pharmaceutically acceptable salt ofsaid compound or of said prodrug and a pharmaceutically acceptablecarrier.

This invention is also directed to pharmaceutical compositions for thetreatment of stroke in a mammal (including a human being) which comprisea stroke treating amount of a compound of Formula I, a prodrug thereof,or a pharmaceutically acceptable salt of said compound or of saidprodrug and a pharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for thetreatment of a myocardial infarction in a mammal (including a humanbeing) which comprise a myocardial infarction treating amount of acompound of Formula I, a prodrug thereof, or a pharmaceuticallyacceptable salt of said compound or of said prodrug and apharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for thetreatment of reperfusion injury in a mammal (including a human being)which comprise a reperfusion injury treating amount of a compound ofFormula I, a prodrug thereof, or a pharmaceutically acceptable salt ofsaid compound or of said prodrug and a pharmaceutically acceptablecarrier.

This invention is also directed to pharmaceutical compositions for thetreatment of angioplastic restenosis in a mammal (including a humanbeing) which comprise an angioplastic restenosis treating amount of acompound of Formula I, a prodrug thereof, or a pharmaceuticallyacceptable salt of said compound or of said prodrug and apharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for thetreatment of hypertension in a mammal (including a human being) whichcomprise a hypertension treating amount of a compound of Formula I, aprodrug thereof, or a pharmaceutically acceptable salt of said compoundor of said prodrug and a pharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for thetreatment of the vascular complications of diabetes in a mammal(including a human being) which comprise a vascular complications ofdiabetes treating amount of a compound of Formula I, a prodrug thereof,or a pharmaceutically acceptable salt of said compound or of saidprodrug and a pharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for thetreatment of obesity in a mammal (including a human being) whichcomprise an obesity treating amount of a compound of Formula l, aprodrug thereof, or a pharmaceutically acceptable salt of said compoundor of said prodrug and a pharmaceutically acceptable carrier.

This invention is also directed to pharmaceutical compositions for thetreatment of endotoxemia in a mammal (including a human being) whichcomprise an endotoxemia treating amount of a compound of Formula I, aprodrug thereof, or a pharmaceutically acceptable salt of said compoundor of said prodrug and a pharmaceutically acceptable carrier.

This invention is also directed to a pharmaceutical combinationcomposition comprising: a therapeutically effective amount of acomposition comprising

a first compound, said first compound being a Formula I compound, aprodrug thereof, or a pharmaceutically acceptable salt of said compoundor of said prodrug;

a second compound, said second compound being an HMG-CoA reductaseinhibitor, an microsomal triglyceride transfer protein (MTP)/Apo Bsecretion inhibitor, a PPAR activator, a bile acid reuptake inhibitor, acholesterol absorption inhibitor, a cholesterol synthesis inhibitor, afibrate, niacin, an ion-exchange resin, an antioxidant, an ACATinhibitor or a bile acid sequestrant; and/or optionally

a pharmaceutical carrier.

Preferred among the second compounds are an HMG-CoA reductase inhibitorand a MTP/Apo B secretion inhibitor.

A particularly preferred HMG-CoA reductase inhibitor is lovastatin,simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin.

Another aspect of this invention is a method for treatingatherosclerosis in a mammal comprising administering to a mammalsuffering from atherosclerosis;

a first compound, said first compound being a Formula I compound aprodrug thereof, or a pharmaceutically acceptable salt of said compoundor of said prodrug; and

a second compound, said second compound being an HMG-CoA reductaseinhibitor, an MTP/Apo B secretion inhibitor, a cholesterol absorptioninhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, anion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acidsequestrant wherein the amounts of the first and second compounds resultin a therapeutic effect.

A preferred aspect of the above method is wherein the second compound isan HMG-CoA reductase inhibitor or an MTP/Apo B secretion inhibitor.

A particularly preferred aspect of the above method is wherein theHMG-CoA reductase inhibitor is lovastatin, simvastatin, pravastatin,fluvastatin, atorvastatin or rivastatin.

Yet another aspect of this invention is a kit comprising:

a. a first compound, said first compound being a Formula I compound, aprodrug thereof, or a pharmaceutically acceptable salt of said compoundor of said prodrug and a pharmaceutically acceptable carrier in a firstunit dosage form;

b. of a second compound, said second compound being an HMG CoA reductaseinhibitor, an MTP/Apo B secretion inhibitor, a cholesterol absorptioninhibitor, a cholesterol synthesis inhibitor, a fibrate, niacin, anion-exchange resin, an antioxidant, an ACAT inhibitor or a bile acidsequestrant and a pharmaceutically acceptable carrier in a second unitdosage form; and

c. means for containing said first and second dosage forms wherein theamounts of the first and second compounds result in a therapeuticeffect.

A preferred second compound is an HMG-CoA reductase inhibitor or anMTP/Apo B secretion inhibitor.

A particularly preferred HMG-CoA reductase inhibitor is lovastatin,simvastatin, pravastatin, fluvastatin, atorvastatin or rivastatin.

As used herein the term mammals is meant to refer to all mammals whichcontain CETP in their plasma, for example, rabbits and primates such asmonkeys and humans. Certain other mammals e.g., dogs, cats, cattle,goats, sheep and horses do not contain CETP in their plasma and so arenot included herein.

The term “treating”, “treat” or “treatment” as used herein includespreventative (e.g., prophylactic) and palliative treatment.

By “pharmaceutically acceptable” is meant the carrier, diluent,excipients, and/or salt must be compatible with the other ingredients ofthe formulation, and not deleterious to the recipient thereof.

The expression “prodrug” refers to compounds that are drug precursorswhich following administration, release the drug in vivo via somechemical or physiological process (e.g., a prodrug on being brought tothe physiological pH or through enzyme action is converted to thedesired drug form). Exemplary prodrugs upon cleavage release thecorresponding free acid, and such hydrolyzable ester-forming residues ofthe Formula I compounds include but are not limited to those having acarboxyl moiety wherein the free hydrogen is replaced by (C₁-C₄)alkyl,(C₂-C₇)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbonatoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N-(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as b-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₁-C₃)alkyl.

The following paragraphs describe exemplary ring(s) for the generic ringdescriptions contained herein.

Exemplary five to six membered aromatic rings optionally having one ortwo heteroatoms selected independently from oxygen, nitrogen and sulfurinclude phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl,pyridiazinyl, pyrimidinyl and pyrazinyl.

Exemplary partially saturated, fully saturated or fully unsaturated fiveto eight membered rings optionally having one to four heteroatomsselected independently from oxygen, sulfur and nitrogen includecyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and phenyl. Furtherexemplary five membered rings include 2H-pyrrolyl, 3H-pyrrolyl,2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, oxazolyl,thiazolyl, imidazolyl, 2H-imidazolyl, 2-imidazolinyl, imidazolidinyl,pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl,1,2-dithiolyl, 1,3-dithiolyl, 3H-1,2-oxathiolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl,1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 3H-1,2,3-dioxazolyl,1,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,3,4-dioxazolyl,5H-1,2,5-oxathiazolyl and 1 ,3-oxathiolyl.

Further exemplary six membered rings include 2H-pyranyl, 4H-pyranyl,pyridinyl, piperidinyl, 1,2-dioxinyl, 1,3-dioxinyl, 1,4-dioxanyl,morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl,pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl,1,2,3-triazinyl, 1,3,5-trithianyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl,6H-1,3-oxazinyl, 6H-1,2-oxazinyl, 1,4-oxazinyl, 2H-1,2-oxazinyl,4H-1,4-oxazinyl, 1,2,5-oxathiazinyl, 1,4-oxazinyl, o-isoxazinyl,p-isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6-oxathiazinyl, 1,4,2-oxadiazinyland 1,3,5,2-oxadiazinyl.

Further exemplary seven membered rings include azepinyl, oxepinyl, andthiepinyl.

Further exemplary eight membered rings include cyclooctyl, cyclooctenyland cyclooctadienyl.

Exemplary bicyclic rings consisting of two fused partially saturated,fully saturated or fully unsaturated five or six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen include indolizinyl,indolyl, isoindolyl, 3H-indolyl, 1H-isoindolyl, indolinyl,cyclopenta(b)pyridinyl, pyrano(3,4b)pyrrolyl, benzofuryl, isobenzofuryl,benzo(b)thienyl, benzo(c)thienyl, 1H-indazolyl, indoxazinyl,benzoxazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl,quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, indenyl, isoindenyl,naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl,pyrido(3,4-b)-pyridinyl, pyrido(3,2-b)-pyridinyl,pyrido(4,3-b)pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl,1H-2,3-benzoxazinyl, 4H-3,1-benzoxazinyl, 2H-1,2-benzoxazinyl and4H-1,4-benzoxazinyl.

By alkylene is meant saturated hydrocarbon (straight chain or branched)wherein a hydrogen atom is removed from each of the terminal carbons.Exemplary of such groups (assuming the designated length encompasses theparticular example) are methylene, ethylene, propylene, butylene,pentylene, hexylene, heptylene).

By halo is meant chloro, bromo, iodo, or fluoro.

By alkyl is meant straight chain saturated hydrocarbon or branched chainsaturated hydrocarbon. Exemplary of such alkyl groups (assuming thedesignated length encompasses the particular example) are methyl, ethyl,propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl,neopentyl, tertiary pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,hexyl, isohexyl, heptyl and octyl.

By alkoxy is meant straight chain saturated alkyl or branched chainsaturated alkyl bonded through an oxy. Exemplary of such alkoxy groups(assuming the designated length encompasses the particular example) aremethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiarybutoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy,isohexoxy, heptoxy and octoxy.

As used herein the term mono-N— or di-N,N-(C₁-C_(x))alkyl . . . refersto the (C₁-C_(x))alkyl moiety taken independently when it isdi-N,N-(C₁-C_(x))alkyl . . . (x refers to integers).

It is to be understood that if a carbocyclic or heterocyclic moiety maybe bonded or otherwise attached to a designated substrate throughdiffering ring atoms without denoting a specific point of attachment,then all possible points are intended, whether through a carbon atom or,for example, a trivalent nitrogen atom. For example, the term “pyridyl”means 2-, 3-, or 4-pyridyl, the term “thienyl” means 2-, or 3-thienyl,and so forth.

References (e.g., claim 1) to “said carbon” in the phrase “said carbonis optionally mono-, di- or tri-substituted independently with halo,said carbon is optionally mono-substituted with hydroxy, said carbon isoptionally mono-substituted with oxo” referes to each of the carbons inthe carbon chain including the connecting carbon.

References to “nitrogen . . . di-substituted with oxo” herein (e.g.,claim 1) refer to a terminal nitrogen which constitutes a nitrofunctionality.

The expression “pharmaceutically-acceptable salt” refers to nontoxicanionic salts containing anions such as (but not limited to) chloride,bromide, iodide, sulfate, bisulfate, phosphate, acetate, maleate,fumarate, oxalate, lactate, tartrate, citrate, gluconate,methanesulfonate and 4-toluene-sulfonate. The expression also refers tonontoxic cationic salts such as (but not limited to) sodium, potassium,calcium, magnesium, ammonium or protonated benzathine(N,N′-dibenzylethylenediamine), choline, ethanolamine, diethanolamine,ethylenediamine, meglamine (N-methyl-glucamine), benethamine(N-benzylphenethylamine), piperazine or tromethamine(2-amino-2-hydroxymethyl-1,3-propanediol).

As used herein, the expressions “reaction-inert solvent” and “inertsolvent” refers to a solvent or a mixture thereof which does notinteract with starting materials, reagents, intermediates or products ina manner which adversely affects the yield of the desired product.

The term “cis” refers to the orientation of two substituents withreference to each other and the plane of the ring (either both “up” orboth “down”). Analogously, the term “trans” refers to the orientation oftwo substituents with reference to each other and the plane of the ring(the substituents being on opposite sides of the ring).

Alpha and Beta refer to the orientation of a substituent with referenceto the plane of the ring (i.e., page). Beta is above the plane of thering (i.e., page) and Alpha is below the plane of the ring (i.e., page).

The chemist of ordinary skill will recognize that certain compounds ofthis invention will contain one or more atoms which may be in aparticular stereochemical or geometric configuration, giving rise tostereoisomers and configurational isomers. All such isomers and mixturesthereof are included in this invention. Hydrates and solvates of thecompounds of this invention are also included.

It will be recognized that the compounds of this invention can exist inradiolabelled form, i.e., said compounds may contain one or more atomscontaining an atomic mass or mass number different from the atomic massor mass number usually found in nature. Radioisotopes of hydrogen,carbon, phosphorous, fluorine and chlorine include ³H, ¹⁴C, ³²P, ³⁵S,¹⁸F and ³⁶Cl, respectively. Compounds of this invention, a prodrugthereof, or a pharmaceutically acceptable salt of said compound or ofsaid prodrug which contain those radioisotopes and/or otherradioisotopes of other atoms are within the scope of this invention.Tritiated, i.e.,³H, and carbon-14, i.e., ¹⁴C, radioisotopes areparticularly preferred for their ease of preparation and detectability.Radiolabelled compounds of Formula I of this invention and prodrugsthereof can generally be prepared by methods well known to those skilledin the art. Conveniently, such radiolabelled compounds can be preparedby carrying out the procedures disclosed in the Schemes and/or in theExamples and Preparations below by substituting a readily availableradiolabelled reagent for a non-radiolabelled reagent.

DTT means dithiothreitol. DMSO means dimethyl sulfoxide. EDTA meansethylenediamine tetraacetic acid.

Other features and advantages of this invention will be apparent fromthis specification and the appendant claims which describe theinvention.

DETAILED DESCRIPTION OF THE INVENTION

In general the compounds of this invention can be made by processeswhich include processes analogous to those known in the chemical arts,particularly in light of the description contained herein. Certainprocesses for the manufacture of the compounds of this invention areprovided as further features of the invention and are illustrated by thefollowing reaction schemes. Other processes may be described in theexperimental section.

As an initial note, in the preparation of the Formula I compounds it isnoted that some of the preparation methods useful for the preparation ofthe compounds described herein may require protection of remotefunctionality (e.g., primary amine, secondary amine, carboxyl in FormulaI precursors). The need for such protection will vary depending on thenature of the remote functionality and the conditions of the preparationmethods. The need for such protection is readily determined by oneskilled in the art. The use of such protection/deprotection methods isalso within the skill in the art. For a general description ofprotecting groups and their use, see T. W. Greene, Protective Groups inOrganic Synthesis, John Wiley & Sons, New York, 1991.

For example, in Reaction Schemes I and II certain Formula I compoundscontain primary amines or carboxylic acid functionalities which mayinterfere with reactions at other sites of the molecule if leftunprotected. Accordingly, such functionalities may be protected by anappropriate protecting group which may be removed in a subsequent step.Suitable protecting groups for amine and carboxylic acid protectioninclude those protecting groups commonly used in peptide synthesis (suchas N-t-butoxycarbonyl, benzyloxycarbonyl, and9-fluorenylmethylenoxycarbonyl for amines and lower alkyl or benzylesters for carboxylic acids) which are generally not chemically reactiveunder the reaction conditions described and can typically be removedwithout chemically altering other functionality in the Formula Icompound.

According to Reaction Scheme I, the Formula III compounds wherein R²,R⁵, R⁶, R⁷, and R⁸ are as described above and P² is an appropriateprotecting group may be prepared from the appropriate Formula IIaromatic amine wherein R⁵, R⁶, R⁷ and R⁸ are as described above.

The Formula III tetrahydroquinoline is prepared by treating theappropriate Formula II aromatic amine with the requisite carboxaldehydein an inert solvent such as a hydrocarbon (e.g., hexanes, pentanes orcyclohexane), an aromatic hydrocarbon (e.g., benzene, toluene orxylene), a halocarbon (e.g., dichloromethane, chloroform, carbontetrachloride or dichloroethane), an ether (e.g., diethyl ether,diisopropyl ether, tetrahydrofuran, tetrahydropyran, dioxane,dimethoxyethane, methyl tert-butyl ether, etc.), a nitrile (e.g.,acetonitrile or propionitrile), a nitroalkane (e.g., nitromethane ornitrobenzene), preferably dichloromethane with a dehydrating agent(e.g., sodium sulfate or magnesium sulfate) at a temperature of about 0°C. to about 100° C. (preferably ambient temperature) for 1-24 hours(preferably 1 hour). The resulting solution is treated with a suitablysubstituted (e.g., benzyloxycarbonyl, t-butoxycarbonyl, methoxycarbonyl,formyl-, acetyl-, diallyl- or dibenzyl-), preferably carboxybenzyloxy-,N-vinyl species and with a Lewis acid (e.g., boron trifluoride, borontrifluoride etherate, zinc chloride, titanium tetrachloride, irontrichloride, aluminum trichloride, alkyl aluminum dichloride, dialkylaluminum chloride or ytterbium (III) triflate; preferably borontrifluoride etherate) or a protic acid such as a hydrohalogenic acid(e.g., fluoro, chloro, bromo or iodo), an alkyl sulfonic acid (e.g.,p-toluene, methane or trifloromethane) or carboxylic acid (e.g., formic,acetic, trifluoroacetic or benzoic) at a temperature of from about −78°C. to about 50° C. (preferably ambient temperature) for 0.1 to 24 hours(preferably 1 hour).

Alternatively, the Formula II amine and appropriate carboxaldehyde maybe condensed by treating a solution of the amine and an alkyl amine base(preferably triethylamine) in a polar aprotic solvent (preferablydichloromethane) with titanium tetrachloride in a polar aprotic solvent(preferably in dichloromethane) at a temperature between about −78° C.to about 40° C. (preferably 0° C.) followed by treatment with thecarboxaldehyde at a temperature between about −78° C. to about 40° C.(preferably 0° C.). The reaction is allowed to proceed for about 0.1 toabout 10 hours (preferably 1 hour) at a temperature between about 0° C.to about 40° C. (preferably room temperature) yielding the imine whichis reacted with the N-vinyl species as above.

The compounds of Formula IV wherein R¹, R², R⁵, R⁶, R⁷ and R⁸ are asdescribed above and P¹ and P² are protecting groups may be prepared fromthe corresponding Formula III amine by various amine reaction routesknown to those skilled in the art.

Thus, the Formula IV compounds wherein R¹, R², R⁵, R⁶, R⁷, and R⁸ are asdescribed above and P¹ and P² are appropriately differentiatedprotecting groups for the amine moieties are prepared from thecorresponding Formula III tetrahydroquinoline employing standard methodsfor derivatizing amines into the functional groups described for R¹above, see Richard Larock, Comprehensive Organic Transformations, VCHPublishers Inc., New York, 1989 and Jerry March, Advanced OrganicChemistry, John Wiley & Sons, New York, 1985. For example, a Formula IIIcompound is treated with the appropriate carbonyl chloride, sulfonylchloride, or sulfinyl chloride, isocyanate or thioisocyanate in a polaraprotic solvent (preferably dichloromethane) in the presence of a base(preferably pyridine) at a temperature of from about −78° C. to about100° C. (preferably starting at 0° C. and letting warm to roomtemperature) for a period of 1 to 24 hours (preferably 12 hours).

Formula IV carbamate and urea compounds (wherein R¹ is W═C(O), X═O—Y,S—Y, N(H)—Y, or NY₂) may be prepared from the Formula III amines via thecorresponding carbamoyl chlorides by treating the Formula III amine witha phosgene solution in a hydrocarbon solvent (preferably toluene) at atemperature between about 0° C. and about 200° C. (preferably at reflux)for between 0.1 and 24 hours (preferably 2 hours).

The corresponding ureas may be prepared by treating a solution of thecarbamoyl chlorides (prepared as described above) with the appropriateamine in a polar solvent (preferably dichloromethane) at a temperaturebetween about −78° C. and about 100° C. (preferably ambient temperature)for between 1 and 24 hours (preferably 12 hours).

The corresponding carbamate may be prepared by treating a solution ofthe carbamoyl chlorides (prepared as described above) with theappropriate alcohol and a suitable base (preferably sodium hydride) in apolar solvent (preferably dioxane) at a temperature between about −78°C. and about 100° C. (preferably ambient temperature) for between 1 and24 hours (preferably 12 hours).

Alternatively, the corresponding carbamate may be prepared by treating asolution of the carbamoyl chlorides at a temperature between about 0° C.and about 200° C. in the appropriate alcohol for between 1 and 240 hours(preferably 24 hours).

The Formula IV compound wherein R¹ is Y may be prepared using methodsknown to those skilled in the art to introduce Y substituents such as analkyl or alkyl linked substituent. Methods include, for example,formation of the amide from the Formula III amine and an activatedcarboxylic acid followed by reduction of the amide with borane in anetheral solvent such as tetrahydrofuran. Alternatively, the alkyl oralkyl linked substituent may be appended by reduction after condensingthe Formula III amine with the required carbonyl containing reactant.Also, the amine may be reacted with the appropriate alkyl or aryl halideaccording to methods known to those skilled in the art.

Thus, the Formula III amine and an acid (e.g., halogenic, sulfuric,sulfonic or carboxylic, preferably acetic) are treated with theappropriate carbonyl containing reactant in a polar solvent (preferablyethanol) at a temperature of about 0° C. to about 100° C. (preferablyroom temperature) for about 0.1 to 24 hours (preferably 1 hour) followedby treatment with a hydride source (e.g., sodium borohydride, sodiumcyanoborohydride, preferably sodium triacetoxyborohydride) at atemperature of about 0° C. to about 100° C. (preferably ambienttemperature) for 0.1 to 100 hours (preferably 5 hours).

The Formula V amine wherein R¹, R², R⁵, R⁶, R⁷, and R⁸ are as describedabove and P¹ is a protecting group may be prepared from thecorresponding Formula IV compound by deprotection (P²) using methodsknown to those skilled in the art, including hydrogenolysis, treatmentwith an acid (e.g., trifluoroacetic acid, hydrobromic), a base (sodiumhydroxide), or reaction with a nucleophile (e.g. sodium methylthiolate,sodium cyanide, etc.) and for the trialkylsilylethoxy carbonyl group afluoride is used (e.g., tetrabutyl ammonium fluoride). For removal of abenzyloxycarbonyl group, hydrogenolysis is performed by treating theFormula IV compound with a hydride source (e.g., 1 to 10 atmospheres ofhydrogen gas, cyclohexene or ammonium formate) in the presence of asuitable catalyst (e.g., 5-20% palladium on carbon, palladium hydroxide;preferably 10% palladium on carbon) in a polar solvent (e.g., methanol,ethanol or ethyl acetate; preferably ethanol) at a temperature betweenabout −78° C. and about 100° C., preferably ambient temperature, for 0.1to 24 hours, preferably 1 hour.

The compounds of Formula VI wherein R¹, R², R³, R⁶, R⁷ and R⁸ are asdescribed above and P¹ is a protecting group as described above may beprepared from the corresponding Formula V amine by various aminereaction routes known to those skilled in the art.

The Formula VI secondary amine wherein R³ is as described above may beprepared using methods known to those skilled in the art to introduce R⁸substituents such as an alkyl or alkyl linked substituent. Methodsinclude, for example, formation of an amide from the Formula V amine andan activated carboxylic acid followed by reduction of the amide withborane in an etheral solvent such as tetrahydrofuran. Alternatively, analkyl or alkyl linked substituent may be appended by reduction of theappropriate imine, the imine being formed by condensing the Formula Vamine with the required carbonyl containing reactant. Also, the FormulaV amine may be reacted with the appropriate alkyl halide according tomethods known to those skilled in the art.

Thus, the Formula V amine and an acid (e.g., halogenic, sulfuric,sulfonic or carboxylic, preferably hydrochloric) are treated with theappropriate carbonyl containing reactant in a polar solvent (preferablydichloromethane) at a temperature of about 0° C. to about 100° C.(preferably room temperature) for about 0.1 to 24 hours (preferably 1hour) followed by treatment with a hydride source (e.g., sodiumborohydride or sodium cyanoborohydride; preferably sodiumtriacetoxyborohydride) at a temperature of about 0° C. to about 100° C.(preferably ambient temperature) for 0.1 to 100 hours (preferably 5hours).

The Formula VII compound wherein R¹, R², R³, R⁵, R⁶, R⁷ and R⁸ are asdescribed above and P¹ and P² are protecting groups may be prepared fromthe corresponding Formula IV compound by methods known to those skilledin the art; for example, the methods described for the introduction ofthe R⁸ substituent above in the transformation of the Formula V compoundto the Formula VI compound. Following this, the corresponding Formula VIcompound may be prepared from the Formula VII compound by appropriatedeprotection such as the methods described above for the transformationof the Formula IV compound to the Formula V compound.

When R³ is H and R⁴ is as described above R⁴ may be represented by R³ inthe Formulas VI and VII in Scheme I, thus providing a synthetic schemefor such compounds.

According to Scheme II, the Formula XI dihydroquinolone compoundswherein R², R⁵, R⁶, R⁷, R⁸ and Y are as described above, and P¹ is aprotecting group, may be prepared from the corresponding Formula Xquinolines by treatment with an organometallic species and achloroformate followed by hydrolysis.

Thus, a mixture of the Formula X quinoline and an excess (preferably 1.5equivalents) of an organomagnesium species (Grignard reagent) in a polaraprotic solvent (e.g., diethyl ether or dichloromethane; preferablytetrahydrofuran) is treated with an excess (preferably 1.5 equivalents)of a Y— or P¹-chloroformate at a temperature between about −100° C. andabout 70° C. (preferably −78° C.) followed by warming to a temperaturebetween about 0° C. and about 70° C. (preferably ambient temperature)for between 0.1 and 24 hours (preferably 1 hour). The resulting mixtureis combined with an excess (preferably 2 equivalents) of an aqueous acid(preferably 1 molar hydrochloric acid) and mixed vigorously for between0.1 and 24 hours (preferably 1 hour, or until hydrolysis of theintermediate enol ether is determined to be complete).

Of course, the Formula XI compounds are the Formula XVI compoundswherein R¹ is —C(O)OY or P¹ is —C(O)OP¹ without further transformation.

The Formula XV compounds wherein R², R⁵, R⁶, R⁷ and R⁸ are as describedabove may be prepared from the corresponding Formula XI dihydroquinolone(wherein compound XI contains P¹) by appropriate deprotection (includingspontaneous decarboxylation) as described for the transformation of theFormula IV compound to the Formula V compound.

The Formula XVI compounds wherein R¹, R², R⁵, R⁶, R⁷ and R⁸ are asdescribed above and P¹ is a protecting group may be prepared from thecorresponding Formula XV dihydroquinolone as described for thetransformation of the Formula III compound to the Formula IV compound.In certain cases where the reagent has also reacted on the 4-positioncarbonyl oxygen, the substituent may be conveniently removed bytreatment with acid (e.g., aqueous HCl) or base (e.g., aqueous sodiumhydroxide).

Again, for those Formula XVI compounds wherein R¹ or P¹ is the same asfor the Formula XI compound such transformation as described above isnot needed.

The Formula VI amine compounds wherein R¹, R², R³, R⁵, R⁶, R⁷ and R⁸ areas described above and P¹ is a protecting group may be prepared from thecorresponding Formula XVI dihydroquinolone by a reductive aminationsequence. The Formula XVI dihydroquinolone, an excess (preferably 1.1equivalents) of an R⁶-amine and an excess (preferably 7 equivalents) ofan amine base (preferably triethylamine) in a polar solvent (preferablydichloromethane) are treated with 0.5 to 1.0 equivalents (preferably0.55 equivalents) of titanium tetrachloride as a solution in a suitablepolar solvent (preferably dichloromethane) at a temperature betweenabout 0° C. and about 40° C. (preferably ambient temperature) forbetween 1 to 24 hours (preferably 12 hours). The resulting Formula XIIimine is reduced by treatment with a reducing agent (preferably sodiumborohydride) in an appropriate polar solvent (preferably ethanol) at atemperature between about 0° C. and about 80° C. (preferably roomtemperature) for between 1 and 24 hours (preferably 12 hours) resultingin a mixture of diastereomeric Formula VI amines, generally favoring thetrans isomer. Alternatively, the reduction may be performed by treatingthe Formula XII imine directly with an excess (preferably 5 equivalents)of zinc borohydride as a solution in ether (preferably 0.2 molar) at atemperature between about 0° C. and about 40° C. (preferably ambienttemperature) for between 1 and 24 hours (preferably 12 hours) resultingin a mixture of diastereomeric Formula VI, amines, generally favoringthe cis isomer.

Alternatively, the Formula VI amine wherein R¹, R², R³, R⁵, R⁶, R⁷ andR⁸ are as described above and P¹ is a protecting group may be preparedfrom the corresponding Formula XVI dihydroquinolones by formation of anoxime, reduction and substitution of the amine. Thus, the Formula XVIdihydroquinolone, excess (preferably 3 equivalents) hydroxylaminehydrochloride and an excess (preferably 2.5 equivalents) of base(preferably sodium acetate) are reacted at a temperature between about0° C. and about 100° C. (preferably at reflux) for between 1 and 24hours (preferably 2 hours) in a polar solvent (preferably ethanol). Theresulting Formula XIII oxime is treated with excess (preferably 6equivalents) aqueous base (preferably 2N potassium hydroxide) in a polarsolvent (preferably ethanol) and an excess (preferably 4 equivalents) ofa nickel-aluminum alloy (preferably 1:1 by weight) at a temperaturebetween about 0° C. and about 100° C. (preferably ambient temperature)for between 0.25 and 24 hours (preferably 1 hour). The resulting FormulaV amine is obtained as a diastereomeric mixture (generally favoring thecis isomer).

The Formula VI secondary amine wherein R¹, R², R³, R⁵, R⁶, R⁷ and R⁸ areas described above and P¹ is a protecting group may be prepared from theappropriate Formula V amine as described in Scheme I for thetransformation of the Formula V compound to the Formula VI compound.

According to Scheme III the Formula I compounds as described above maybe prepared from the appropriate Formula VI compounds by conversion tothe desired carbamate. Thus, the Formula VI amine is treated with theappropriate activated carbonate (e.g., chloroformate, dicarbonate orcarbonyl diimidazole followed by the appropriate alcohol) in a polarsolvent (preferably dichloromethane) in the presence of an excess ofamine base (preferably pyridine) at a temperature between about −20° C.and about 40° C. (preferably ambient temperature) for between 1 and 24hours (preferably 12 hours) to yield the Formula I compound.

Alternatively, according to Scheme III, where appropriate, if thefunctionality at R¹ is incompatible with the reaction to form theFormula I compound, then the P protected Formula VI compound may betransformed to the Formula I compound through protection/deprotectionsequences and introduction of the desired substituents. Thus, theFormula VI amine is treated with the appropriate reagent (e.g.,protecting group precursor, activated carbonate (e.g., chloroformate,dicarbonate or carbonyl imidazole)) in a polar solvent (preferablydichloromethane) in the presence of an excess of amine base (preferablypyridine) at a temperature between about −20° C. and about 40° C.(preferably ambient temperature) for between 1 and 24 hours (preferably12 hours) to yield the Formula XX compound .

Also, the Formula XX compounds, wherein P² is present may be obtained asshown in Scheme I for the Formula VII compounds (having P¹).

The Formula XXI amines wherein R², R³, R⁵, R⁶, R⁷, R⁸ and R⁴ are asdescribed above and P² is a protecting group may be prepared from theFormula XX compound by selective deprotection of P¹.

When P¹ is, for example, t-butoxycarbonyl, the Formula XXI compound isconveniently prepared by treatment with an acid (preferablytrifluoroacetic acid)) at a temperature between about 0° C. and about100° C. (preferably room temperature) for 0.1 to 24 hours (preferably 1hour).

The compounds of Formula I or compounds of Formula XXII (wherein R¹ isas described above) may be prepared from the corresponding Formula XXIamine (wherein R⁴ or P² is present respectively) by various aminereaction routes known to those skilled in the art; for example, thosedescribed in Scheme I for the transformation of the Formula III compoundto the Formula IV compound.

The Formula XXIII amines may be prepared from the Formula XXII compoundsby suitable deprotection. When P² is, for example, benzyloxycarbonyl,the Formula XXII compound is prepared by treatment with an excess of ahydride source (e.g., cyclohexene, hydrogen gas or preferably ammoniumformate) in the presence of 0.01 to 2 equivalents (preferably 0.1equivalent) of a suitable catalyst (preferably 10% palladium on carbon)in a polar solvent (preferably ethanol) at a temperature between about0° C. and about 100° C. (preferably room temperature) for 0.1 to 24hours (preferably 1 hour).

The Formula I compound wherein R⁴ is as described above may be preparedusing the methods described for the conversion of the Formula VIcompound to the Formula I compound in Scheme III above.

According to Scheme IV the Formula V compounds wherein R¹, R², R⁵, R⁷and R⁸ are as described above, and R⁶ is an ether linked moiety can beobtained from the Formula XXX quinolones having a OP³ moiety, wherein P³is a protecting group, at the R⁶ position employing the followingmethods. In addition, in an analogous manner such processes may be usedto prepare the corresponding compounds wherein R⁶, R⁷, or R⁸ are anether linked moiety starting from the corresponding Formula XXX compoundhaving an OP³ moiety at either the R⁵, R⁷, or R⁸ positions.

Thus, the Formula XXX quinolone is combined with hydroxylaminehydrochloride and a mineral base (preferably sodium acetate) in a polarsolvent (preferably ethanol) at a temperature between about 0° C. andabout 100° C. (preferably at reflux) for between 1 and 24 hours(preferably 2 hours) to yield the Formula XXXI oxime.

The Formula XXXI oxime is treated with an excess (preferably sixequivalents) of an aqueous base (preferably 2N potassium hydroxide) andan excess (preferably four equivalents) of a nickel-aluminum alloy(preferably 1:1 by weight) in a polar solvent (preferably ethanol) at atemperature between about 0° C. and about 100° C. (preferably ambienttemperature) for between 0.25 and 24 hours (preferably 2 hours) toprepare the corresponding Formula XXXII amine. If necessary, the P³protecting group may be removed using standard methods if the oximetransformation does not result in such cleavage.

Alternatively, the Formula XXX compound may be deprotected (removal ofthe P³) by methods known to those skilled in the art prior to formationof the Formula XXXI oxime (wherein P³ is H) which can then be reduced toform the Formula XXXII amine.

The Formula V compound wherein R⁶ is an oxy-linked moiety may beprepared by treating the Formula XXXII alcohol under, for example,Mitsunobu conditions. Thus, the Formula XXXII phenol is treated with aphosphine (preferably triphenylphosphine) and an azodicarboxylate(preferably bis-(N-methylpiperazinyl)azodicarboxamide) and the requiredalcohol in a polar solvent (preferably benzene).

Of course, via Schemes I and II the resulting Formula V compound may betransformed into the Formula VI precursors for the Formula I compoundsof this invention.

Alternatively, the Formula XX compound wherein R⁶ is an ether linkedmoiety and wherein R¹, R², R³ and R⁴ are as described above and P¹ andP² are protecting groups may be prepared from the Formula XXXII alcoholsas described below. In addition, in an analogous manner such processesmay be used to prepare the corresponding compounds wherein R⁵, R⁷, or R⁸are an ether linked moiety starting from the corresponding Formula XXXIIcompound and thus ultimately the Formula XXX compound (i.e., the FormulaXXX compound having a P³O— at either the R⁵, R⁷, or R⁸ positions).

The Formula XXXIII secondary amine wherein R³ is as described above maybe prepared from the corresponding Formula XXXII compound according tomethods in Scheme I described above for the conversion of the Formula Vcompound to the Formula VI compound.

The Formula XXXIV compounds wherein R⁴ is as described above may beprepared from Formula XXXIII amines by methods analogous to thatdescribed in Scheme III for the transformation of the Formula VIcompound to the Formula I compound.

The Formula XXXV phenol may be selectively deprotected for example whenR⁴O₂CO— is present by treating the Formula XXXIV carbonate withpotassium carbonate in a polar solvent (preferably methanol) at atemperature between about 0° C. and about 100° C. (preferably ambienttemperature) for between 1 and 24 hours (preferably 12 hours).

The corresponding XX ethers may be prepared from the Formula XXXV phenolusing, for example, the Mitsunobu conditions described above for theconversion of the Formula XXXII compounds to the Formula V compounds.

Of course one skilled in the art will appreciate that the phenol may bederivatized to a variety of functional groups using standard methods,for example, as described in March or Larock, or by conversion to thecorresponding triflate for use in a variety of reactions involvingtransition metal catalysis.

Although the following description of Scheme V is directed tomodifications of the R⁶ position (the R⁶ position described in Formula Iabove) those skilled in the art will appreciate that analogous methodsmay be applied to the R⁵, R⁷ and R⁸ positions.

According to Scheme V the Formula LI alcohol wherein R¹, R², R³, R⁴, R⁵,R⁷ and R⁸ are as described above, P¹ and P² are protecting groups, andX¹ is a linking group wherein a carbon (e.g., methylene) is directlylinked to the carbonyl moiety may be prepared from the correspondingester (wherein R¹² is a convenient alkyl moiety) by reduction.

Thus, the Formula L ester is treated with sodium borohydride/methanol ora borane-dimethylsulfide complex in a polar solvent (preferablytetrahydrofuran) at a temperature between about 0° C. and about 100° C.(preferably at reflux) for between 1 and 24 hours (preferably 3 hours).

The Formula LII compounds wherein R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ are asdescribed above, P¹ and P² are protecting groups and wherein the R⁶position includes an alkyl halide functionality may be prepared from thecorresponding Formula LI alcohol by treatment with a trialkylphosphine(preferably triphenylphosphine) and a dihalogen (e.g., bromine) in apolar solvent (preferably dichloromethane) at a temperature betweenabout −78° C. and about 100° C. (preferably 0° C.) for between 0.1 and10 hours (preferably 0.5 hours) followed by warming to room temperaturefor between 0.1 and 10 hours (preferably 3 hours).

The Formula LIII compounds wherein R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ are asdescribed above, P¹ and P² are protecting groups, the R⁶ positionincludes ether or thioether moieties (i.e., Y¹ is S or O) and R¹³ is acarbon linked substituent may be prepared by treating the Formula LIIalkyl halide in a polar solvent (preferably N,N-dimethylformamide) withthe requisite alkoxide or thioalkoxide at a temperature between about 0°C. and about 100° C. (preferably at room temperature) for between 1 and24 hours (preferably 6 hours).

Alternatively, the Formula LIII ethers and thioethers may be prepared bytreating the corresponding Formula LIV alcohols and thiols (i.e., Y¹ isS or O), wherein X¹ is a substituent linked directly through carbon tothe methylene moiety, with a base (preferably sodium hydride) and therequisite alkylating agent in a polar solvent (preferablyN,N-dimethylformamide) at a temperature between about 0° C. and about100° C. (preferably at room temperature) for between 1 and 50 hours(preferably 18 hours).

The Formula LV compounds wherein R¹, R², R³, R⁴, R⁵, R⁷ and R⁸ are asdescribed above, P¹ and P² are protecting groups, the R⁶ positionincludes alkyl halides (e.g., fluorides) and X¹ is a substituent that iscarbon linked directly to the methylene moiety may be prepared bytreating the corresponding Formula LI alcohol with a halogenating agent.For example, the alcohol is treated with a fluorinating agent(preferably diethylaminosulfur trifluoride) in a polar solvent(preferably 1,2-dichloroethane) at a temperature between about 0° C. andabout 100° C. (preferably 80° C.) for between 0.1 and 10 hours(preferably 0.75 hours).

The Formula LVII amide compounds wherein R¹, R², R³, R⁴, R⁵, R⁷ and R⁸are as described above, P¹ and P² are protecting groups and wherein R⁶includes an amide functionality (such that X is a substituent that iscarbon linked directly to the carbonyl moiety and R¹⁰ and R¹¹ aresubstituents selected to yield the desired R⁶ substituent defined above)may be prepared from the corresponding Formula LVI carboxylic acid whichmay in turn be prepared from the corresponding Formula L carboxylicester.

Thus, the Formula L ester is treated with an aqueous hydroxide(preferably lithium, sodium or potassium) in a polar solvent (preferablytetrahydrofuran and/or methanol) at a temperature between about 0° C.and about 100° C. (preferably room temperature) for between 0.1 and 100hours (preferably 1 hour).

The Formula LVII amide may be prepared from the corresponding FormulaLVI acid by standard methods. Preferred is conversion of the carboxylicacid to the acid chloride by dissolving the acid in thionyl chloride andmaintaining the solution at a temperature between about 0° C. and about80° C. (preferably at reflux) for between 0.1 and 24 hours (preferably 1hour) before evaporation of the excess thionyl chloride. This step isfollowed by treating the resulting acid chloride residue in a polarsolvent (preferably dichloromethane) with the appropriate amine,selected to yield the amide functionality, and optionally an amine base(preferably triethylamine) at a temperature between about −78° C. andabout 100° C. (preferably room temperature) for between 0.1 and 100hours (preferably 1 hour).

Although the following description of Scheme VI is directed tomodifications of the R⁸ position those skilled in the art willappreciate that analogous methods may be applied to the R⁵, R⁶ and R⁷positions.

According to Scheme VI the Formula LXI compound wherein R¹, R², R³, R⁴,R⁵, R⁶, and R⁷ are as described above and P¹ and P² are protectinggroups may be prepared from the corresponding Formula LX compound bynitration. The Formula LX compound is treated with nitrosyltriflate in ahalogenated solvent, such as dichloromethane at a temperature of about−78° C. to about 0° C. for about 0.5 hour to about 3 hours followed bywarming to ambient temperature.

The Formula LXII amine wherein R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are asdescribed above and P¹ and P² are protecting groups may be prepared fromthe corresponding Formula LXI compound by reduction. The Formula LXIcompound is hydrogenated by treatment with hydrogen gas in the presenceof a noble metal catalyst (e.g., palladium on carbon) in a polar solventsuch as ethanol at a temperature of about 0° C. to about 100° C. forabout 1 to 24 hours at elevated pressure (e.g., 1 to 3 atmospheres).

The Formula LXIII compound wherein R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are asdescribed above, P¹ and P² are protecting groups and R⁸ is an aminelinked functionality may be prepared from the corresponding FormulaLXII.

Briefly, the Formula LXII amine is derivatized following proceduresanalogous to those described in Scheme I for the conversion of theFormula III compound to the Formula IV compound.

The Formula LXIV compound wherein R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ are asdescribed above and P¹ and P² are protecting groups may be prepared fromthe corresponding Formula LXII compound. The Formula LXII amine istreated with t-butyl nitrate and anhydrous cupric halide in a polarsolvent at a temperature of about 30° C. to about 100° C. for about 1hour to about 24 hours.

Of course, one skilled in the art will understand that the halide may bederivatized to a variety of functional groups using standard methods,for example, as described in Larock or March.

According to Scheme VII the Formula LXXI heterocycles wherein R¹, R²,R³, R⁴, R⁵ and R⁸ are as described above, P¹ and P² are protectinggroups and R²⁰ is a nitrogen containing heterocycle fused to thequinoline ring structure, may be prepared from the Formula LXX compound,wherein P³ is a protecting group, by selective deprotection.

When P³ is for example, benzyloxycarbonyl, the Formula LXX compound isconveniently cleaved to yield the Formula LXXI compound by treatmentwith a hydrogen source (preferably 3 atmospheres of hydrogen gas) in thepresence of a suitable catalyst (preferably 10% palladium on carbon) ina polar solvent (preferably ethanol) at a temperature between about 0°C. and about 100° C. (preferably room temperature) for 0.1 to 24 hours(preferably 1 hour).

The compounds of Formula LXXII, wherein R¹, R², R³, R⁴, R⁵ and R⁸ are asdescribed above, P¹ and P² are protecting groups, R²⁰ is a nitrogencontaining heterocycle fused to the quinoline ring structure, and the“Substituent” is selected to afford the desired compounds describedabove, may be prepared from the corresponding Formula LXXI amine byvarious amine reaction routes known to those skilled in the art; forexample, those described in Scheme I for the transformation of theFormula III compounds to the Formula IV compounds.

The compounds of Formula LXX may be prepared according to the methodsdescribed in Schemes I, II and III. For example, in Scheme II thequinolines of Formula X are formed by methods known to those skilled inthe art from the arylamines of Formula II wherein R⁵ and R⁶, R⁶ and R⁷,or R⁷ and R⁸ comprise a ring as described above. These bicyclicarylamines are also synthesized by a variety of methods known to thoseskilled in the art. Such bicyclic arylamines are used in the sequence oftransformations as illustrated in Schemes I and III to prepare thedesired compounds.

The compounds of Formula LXX may also be obtained from compounds ofFormula I, wherein R⁵ and R⁶, R⁶ and R⁷, or R⁷ and R⁸ containfunctionality amenable to cyclization, for example according to SchemeVIII, thus forming the desired ring, employing methods known to thoseskilled in the art to cyclize such substituents.

For example, the Formula LXXXII compound of Scheme VIII is reacted withP³NH₂ to give the P³ protected isoindoline.

According to Scheme VIII the Formula LXXX diesters are reduced affordingthe corresponding Formula LXXXI dialcohols according to methodsanalogous to those described in Scheme V for the transformation of theFormula L compounds to the Formula LI compounds. Activation of thesealcohols for electrophillic attack may be achieved by a number ofstandard methods, such as conversion to a halide or sulfonate(preferably conversion to the Formula LXXXII bis-bromide by treatmentwith two equivalents of dibromotriphenylphosphorane). Formation of theFormula LXXXIII thiacycle may be achieved by treatment of thebis-bromide with a sulfide (preferably sodium sulfide) in anaqueous/organic immiscible solvent system (preferably a water andtoluene mixture) containing a suitable phase transfer catalyst(preferably triethylhexylammonium bromide) at a temperature betweenabout 0° C. and about 100° C. (preferably room temperature) for between1 and 100 hours (preferably 12 hours).

The Formula LXXXIV oxygen heterocycles may be formed using standardetherification methods including a nucleophillic displacement reactionwith an appropriate bis-electrophile from the corresponding FormulaLXXXII compound. For example, formation of the oxacycle may be achievedby treatment of a bis-bromide in an aqueous immiscible solvent(preferably benzene) with an aqueous hydroxide solution (preferably 30%sodium hydroxide) containing a suitable phase transfer catalyst(preferably benzyl tri-n-butylammonium chloride) at a temperaturebetween about 0° C. and about 100° C. (preferably 80° C.) for between 1and 100 hours (preferably 4 hours).

The Formula LXXXV and LXXXVI lactones, wherein R¹, R², R³, R⁴, R⁵ and R⁸are as described above and P¹ and P² are protecting groups, may beformed using standard lactonization methods including an oxidativecyclization of the corresponding Formula LXXXI dialcohol. Thus, asuitable bis-alcohol is treated with an oxidizing agent (preferablypyridinium chlorochromate) in a polar aprotic solvent (preferablydichloromethane) at a temperature between about 0° C. and about 100° C.(conveniently room temperature) for between 1 and 100 hours (preferably24 hours) to prepare a mixture of the Formula LXXXV and Formula LXXXVIlactones which may be separated by standard methods.

Prodrugs of the compounds of Formula I may be prepared according tomethods known to those skilled in the art. Exemplary processes aredescribed below.

Prodrugs of this invention where a carboxyl group in a carboxylic acidof Formula I is replaced by an ester may be prepared by combining thecarboxylic acid with the appropriate alkyl halide in the presence of abase such as potassium carbonate in an inert solvent such asdimethylformamide at a temperature of about 0 to 100° C. for about 1 toabout 24 hours. Alternatively the acid is combined with appropriatealcohol as solvent in the presence of a catalytic amount of acid such asconcentrated sulfuric acid at a temperature of about 20 to 100° C.,preferably at a reflux, for about 1 hour to about 24 hours. Anothermethod is the reaction of the acid with a stoichiometric amount of thealcohol in the presence of a catalytic amount of add in an inert solventsuch as toluene or tetrahydrofuran, with concomitant removal of thewater being produced by physical (e.g., Dean-Stark trap) or chemical(e.g., molecular sieves) means.

Prodrugs of this invention where an alcohol function has beenderivatized as an ether may be prepared by combining the alcohol withthe appropriate alkyl bromide or iodide in the presence of a base suchas potassium carbonate in an inert solvent such as dimethylformamide ata temperature of about 0 to 100° C. for about 1 to about 24 hours.Alkanoylaminomethyl ethers may be obtained by reaction of the alcoholwith a bis-(alkanoylamino)methane in the presence of a catalytic amountof acid in an inert solvent such as tetrahydrofuran, according to amethod described in U.S. Pat. No. 4,997,984. Alternatively, thesecompounds may be prepared by the methods described by Hoffman et al. inJ. Org. Chem. 1994, 59, 3530.

Glycosides are prepared by reaction of the alcohol and a carbohydrate inan inert solvent such as toluene in the presence of add. Typically thewater formed in the reaction is removed as it is being formed asdescribed above. An alternate procedure is the reaction of the alcoholwith a suitably protected glycosyl halide in the presence of basefollowed by deprotection.

N-(1-hydroxyalkyl)amides, N-(1-hydroxy-1-(alkoxycarbonyl)methyl) amidesmay be prepared by the reaction of the parent amide with the appropriatealdehyde under neutral or basic conditions (e.g., sodium ethoxide inethanol) at temperatures between 25 and 70° C. N-alkoxymethyl orN-1-(alkoxy)alkyl derivatives can be obtained by reaction of theN-unsubstituted compound with the necessary alkyl halide in the presenceof a base in an inert solvent.

The compounds of this invention may also be used in conjunction withother pharmaceutical agents (e.g., LDL-cholesterol lowering agents,triglyceride lowering agents) for the treatment of thedisease/conditions described herein. For example, they may be used incombination with cholesterol synthesis inhibitors, cholesterolabsorption inhibitors, MTP/Apo B secretion inhibitors, and othercholesterol lowering agents such as fibrates, niacin, ion-exchangeresins, antioxidants, ACAT inhibitors and bile acid sequestrants. Incombination therapy treatment, both the compounds of this invention andthe other drug therapies are administered to mammals (e.g., humans, maleor female) by conventional methods.

Any HMG-CoA reductase inhibitor may be used as the second compound inthe combination aspect of this invention. The term HMG-CoA reductaseinhibitor refers to compounds which inhibit the bioconversion ofhydroxymethylglutaryl-coenzyme A to mevalonic acid catalyzed by theenzyme HMG-CoA reductase. Such inhibition is readily determined by thoseskilled in the art according to standard assays (e.g., Meth. Enzymol.1981; 71:455-509 and references cited therein). A variety of thesecompounds are described and referenced below however other HMG-CoAreductase inhibitors will be known to those skilled in the art. U.S.Pat. No. 4,231,938 (the disclosure of which is hereby incorporated byreference) discloses certain compounds isolated after cultivation of amicroorganism belonging to the genus Aspergillus, such as lovastatin.Also, U.S. Pat. No. 4,444,784 (the disclosure of which is herebyincorporated by reference) discloses synthetic derivatives of theaforementioned compounds, such as simvastatin. Also, U.S. Pat. No.4,739,073 (the disclosure of which is incorporated by reference)discloses certain substituted indoles, such as fluvastatin. Also, U.S.Pat. No. 4,346,227 (the disclosure of which is incorporated byreference) discloses ML-236B derivatives, such as pravastatin. Also,EP-491226A (the disclosure of which is incorporated by reference)discloses certain pyridyldihydroxyheptenoic adds, such as rivastatin. Inaddition, U.S. Pat. No. 5,273,995 (the disclosure of which isincorporated by reference) discloses certain6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-ones such as atorvastatin.

Any MTP/Apo B secretion (microsomal triglyceride transfer protein and orapolipoprotein B) inhibitor may be used as the second compound in thecombination aspect of this invention. The term MTP/Apo B secretioninhibitor refers to compounds which inhibit the secretion oftriglycerides, cholesteryl ester, and phospholipids. Such inhibition isreadily determined by those skilled in the art according to standardassays (e.g., Wetterau, J. R. 1992; Science 258:999). A variety of thesecompounds are described and referenced below however other MTP/Apo Bsecretion inhibitors will be known to those skilled in the art.

WO 96/40640 and WO 98/23593 are two exemplary publications.

For example, the following MTP/Apo B secretion inhibitors areparticularly useful:

4′-trifluoromethyl-biphenyl-2-carboxylic acid[2-(1H-[1,2,4,]triazol-3-ylmethyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide;

4′-trifluoromethyl-biphenyl-2-carboxylic acid[2-(2-acetylamino-ethyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide;

(2-{6-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H-isoquinolin-2-yl}-ethyl)-carbamicacid methyl ester;

4′-trifluoromethyl-biphenyl-2-carboxylic acid[2-(1H-imidazol-2-ylmethyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide;

4′-trifluoromethyl-biphenyl-2-carboxylic acid[2-(2,2-diphenyl-ethyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide; and

4′-trifluoromethyl-biphenyl-2-carboxylic acid[2-(2-ethoxy-ethyl)-1,2,3,4-tetrahydro-isoquinolin-6-yl]-amide.

Any HMG-CoA synthase inhibitor may be used as the second compound in thecombination aspect of this invention. The term HMG-CoA synthaseinhibitor refers to compounds which inhibit the biosynthesis ofhydroxymethylglutaryl-coenzyme A from acetyl-coenzyme A andacetoacetyl-coenzyme A, catalyzed by the enzyme HMG-CoA synthase. Suchinhibition is readily determined by those skilled in the art accordingto standard assays (Meth Enzymol. 1975; 35:155-160: Meth. Enzymol. 1985;110:19-26 and references cited therein). A variety of these compoundsare described and referenced below, however other HMG-CoA synthaseinhibitors will be known to those skilled in the art. U.S. Pat. No.5,120,729 (the disclosure of which is hereby incorporated by reference)discloses certain beta-lactam derivatives. U.S. Pat. No. 5,064,856 (thedisclosure of which is hereby incorporated by reference) disclosescertain spiro-lactone derivatives prepared by culturing a microorganism(MF5253). U.S. Pat. No. 4,847,271 (the disclosure of which is herebyincorporated by reference) discloses certain oxetane compounds such as11-(3-hydroxymethyl-4-oxo-2-oxetayl)-3,5,7-trimethyl-2,4-undeca-dienoicacid derivatives.

Any compound that decreases HMG-CoA reductase gene expression may beused as the second compound in the combination aspect of this invention.These agents may be HMG-CoA reductase transcription inhibitors thatblock the transcription of DNA or translation inhibitors that preventtranslation of mRNA coding for HMG-CoA reductase into protein. Suchcompounds may either affect transcription or translation directly, ormay be biotransformed to compounds that have the aforementionedactivities by one or more enzymes in the cholesterol biosyntheticcascade or may lead to the accumulation of an isoprene metabolite thathas the aforementioned activities. Such regulation is readily determinedby those skilled in the art according to standard assays (Meth. Enzymol.1985; 110:9-19). Several compounds are described and referenced below,however other inhibitors of HMG-CoA reductase gene expression will beknown to those skilled in the art. U.S. Pat. No. 5,041,432 (thedisclosure of which is incorporated by reference) discloses certain15-substituted lanosterol derivatives. Other oxygenated sterols thatsuppress synthesis of HMG-CoA reductase are discussed by E. I. Mercer(Prog. Lip. Res. 1993; 32:357-416).

Any squalene synthetase inhibitor may be used as the second compound ofthis invention. The term squalene synthetase inhibitor refers tocompounds which inhibit the condensation of 2 molecules offarnesylpyrophosphate to form squalene, catalyzed by the enzyme squalenesynthetase. Such inhibition is readily determined by those skilled inthe art according to standard assays (Meth. Enzymol. 1969; 15: 393-454and Meth. Enzymol. 1985; 110:359-373 and references contained therein).A variety of these compounds are described in and referenced belowhowever other squalene synthetase inhibitors will be known to thoseskilled in the art. U.S. Pat. No. 5,026,554 (the disclosure of which isincorporated by reference) discloses fermentation products of themicroorganism MF5465 (ATCC 74011) including zaragozic add. A summary ofother patented squalene synthetase inhibitors has been compiled (Curr.Op. Ther. Patents (1993) 861-4).

Any squalene epoxidase inhibitor may be used as the second compound inthe combination aspect of this invention. The term squalene epoxidaseinhibitor refers to compounds which inhibit the bioconversion ofsqualene and molecular oxygen into squalene-2,3-epoxide, catalyzed bythe enzyme squalene epoxidase. Such inhibition is readily determined bythose skilled in the art according to standard assays (Biochim. Biophys.Acta 1984; 794:466-471). A variety of these compounds are described andreferenced below, however other squalene epoxidase inhibitors will beknown to those skilled in the art. U.S. Pat. Nos. 5,011,859 and5,064,864 (the disclosures of which are incorporated by reference)disclose certain fluoro analogs of squalene. EP publication 395,768 A(the disclosure of which is incorporated by reference) discloses certainsubstituted allylamine derivatives. PCT publication WO 9312069 A (thedisclosure of which is hereby incorporated by reference) disclosescertain amino alcohol derivatives. U.S. Pat. No. 5,051,534 (thedisclosure of which is hereby incorporated by reference) disclosescertain cyclopropyloxy-squalene derivatives.

Any squalene cyclase inhibitor may be used as the second component inthe combination aspect of this invention. The term squalene cyclaseinhibitor refers to compounds which inhibit the bioconversion ofsqualene-2,3-epoxide to lanosterol, catalyzed by the enzyme squalenecyclase. Such inhibition is readily determined by those skilled in theart according to standard assays (FEBS Lett. 1989; 244:347-350.). Inaddition, the compounds described and referenced below are squalenecyclase inhibitors, however other squalene cyclase inhibitors will alsobe known to those skilled in the art. PCT publication WO9410150 (thedisclosure of which is hereby incorporated by reference) disclosescertain1,2,3,5,6,7,8,8α-octahydro-5,5,8α(beta)-trimethyl-6-isoquinolineaminederivatives, such asN-trifluoroacetyl-1,2,3,5,6,7,8,8α-octahydro-2-allyl-5,5,8α(beta-trimethyl-6(beta)-isoquinolineamine.French patent publication 2697250 (the disclosure of which is herebyincorporated by reference) discloses certain beta,beta-dimethyl-4-piperidine ethanol derivatives such as1-(1,5,9-trimethyldecyl)-beta,beta-dimethyl-4-piperidineethanol.

Any combined squalene epoxidase/squalene cyclase inhibitor may be usedas the second component in the combination aspect of this invention. Theterm combined squalene epoxidase/squalene cyclase inhibitor refers tocompounds that inhibit the bioconversion of squalene to lanosterol via asqualene-2,3-epoxide intermediate. In some assays it is not possible todistinguish between squalene epoxidase inhibitors and squalene cyclaseinhibitors, however, these assays are recognized by those skilled in theart. Thus, inhibition by combined squalene epoxidase/squalene cyclaseinhibitors is readily determined by those skilled in art according tothe aforementioned standard assays for squalene cyclase or squaleneepoxidase inhibitors. A variety of these compounds are described andreferenced below, however other squalene epoxidase/squalene cyclaseinhibitors will be known to those skilled in the art. U.S. Pat. Nos.5,084,461 and 5,278,171 (the disclosures of which are incorporated byreference) disclose certain azadecalin derivatives. EP publication468,434 (the disclosure of which is incorporated by reference) disclosescertain piperidyl ether and thio-ether derivatives such as2-(1-piperidyl)pentyl isopentyl sulfoxide and 2-(1-piperidyl)ethyl ethylsulfide. PCT publication WO 9401404 (the disclosure of which is herebyincorporated by reference) discloses certain acyl-piperidines such as1-(1-oxopentyl-5-phenylthio)-4-(2-hydroxy-1-methyl)-ethyl)piperidine.U.S. Pat. No. 5,102,915 (the disclosure of which is hereby incorporatedby reference) discloses certain cyclopropyloxy-squalene derivatives.

The starting materials and reagents for the above described Formula Icompounds, are also readily available or can be easily synthesized bythose skilled in the art using conventional methods of organicsynthesis. For example, many of the compounds used herein, are relatedto, or are derived from compounds in which there is a large scientificinterest and commercial need, and accordingly many such compounds arecommercially available or are reported in the literature or are easilyprepared from other commonly available substances by methods which arereported in the literature.

Some of the Formula I compounds of this invention or intermediates intheir synthesis have asymmetric carbon atoms and therefore areenantiomers or diastereomers. Diasteromeric mixtures can be separatedinto their individual diastereomers on the basis of their physicalchemical differences by methods known per se., for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by, for example, chiral HPLC methods or converting theenantiomeric mixture into a diasteromeric mixture by reaction with anappropriate optically active compound (e.g., alcohol), separating thediastereomers and converting (e.g., hydrolyzing) the individualdiastereomers to the corresponding pure enantiomers. Also, anenantiomeric mixture of the Formula I compounds or an intermediate intheir synthesis which contain an acidic or basic moiety may be separatedinto their compounding pure enantiomers by forming a diastereomeric saltwith an optically pure chiral base or acid (e.g., 1-phenyl-ethyl amineor tahtaric acid) and separating the diasteromers by fractionalcrystallization follwed by neutralization to break the salt, thusproviding the corresponding pure enantiomers. All such isomers,including diastereomers, enantiomers and mixtures thereof are consideredas part of this invention. Also, some of the compounds of this inventionare atropisomers (e.g., substituted biaryls) and are considered as partof this invention.

More specifically, the Formula I compounds of this invention may beobtained in enantiomerically enriched form by resolving the racemate ofthe final compound or an intermediate in its synthesis (preferably thefinal compound) employing chromatography (preferably high pressureliquid chromatography [HPLC]) on an asymmetric resin (preferablyChiralcel™ AD or OD [obtained from Chiral Technologies, Exton, Pa.])with a mobile phase consisting of a hydrocarbon (preferably heptane orhexane) containing between 0 and 50% isopropanol (preferably between 2and 20%) and between 0 and 5% of an alkyl amine (preferably 0.1% ofdiethylamine). Concentration of the product containing fractions affordsthe desired materials.

Some of the Formula I compounds of this invention are acidic and theyform a salt with a pharmaceutically acceptable cation. Some of theFormula I compounds of this invention are basic and they form a saltwith a pharmaceutically acceptable anion. All such salts are within thescope of this invention and they can be prepared by conventional methodssuch as combining the acidic and basic entities, usually in astoichiometric ratio, in either an aqueous, non-aqueous or partiallyaqueous medium, as appropriate. The salts are recovered either byfiltration, by precipitation with a non-solvent followed by filtration,by evaporation of the solvent, or, in the case of aqueous solutions, bylyophilization, as appropriate. The compounds can be obtained incrystalline form by dissolution in an appropriate solvent(s) such asethanol, hexanes -an or water/ethanol mixtures.

In addition, when the Formula I compounds of this invention formhydrates or solvates they are also within the scope of the invention.

The Formula I compounds of this invention, their prodrugs and the saltsof such compounds and prodrugs are all adapted to therapeutic use asagents that inhibit cholesterol ester transfer protein activity inmammals, particularly humans. Thus, the compounds of this inventionelevate plasma HDL cholesterol, its associated components, and thefunctions performed by them in mammals, particularly humans. By virtueof their activity, these agents also reduce plasma levels oftriglycerides, VLDL cholesterol LDL cholesterol and their associatedcomponents in mammals, particularly humans. Hence, these compounds areuseful for the treatment and correction of the various dyslipidemiasobserved to be associated with the development and incidence ofatherosclerosis and cardiovascular disease, includinghypoalphalipoproteinemia, hyperbetalipoproteinemia,hypertriglyceridemia, and familial-hypercholesterolemia.

Further, introduction of a functional CETP gene into an animal lackingCETP (mouse) results in reduced HDL levels (Agellon, L. B., et al: J.Biol. Chem. (1991) 266: 10796-10801.) and increased susceptibility toatherosclerosis. (Marotti, K. R., et al: Nature (1993) 364: 73-75.).Also, inhibition of CETP activity with an inhibitory antibody raisesHDL-cholesterol in hamster (Evans, G. F., et al: J. of Lipid Research(1994) 35: 1634-1645.) and rabbit (Whitlock, M. E., et al: J. Clin.Invest. (1989) 84: 129-137). Suppression of increased plasma CETP byintravenous injection with antisense oligodeoxynucleotides against CETPmRNA reduced atherosclerosis in cholesterol-fed rabbits (Sugano, M., etal: J. of Biol. Chem. (1998) 273: 5033-5036.) Importantly, humansubjects deficient in plasma CETP, due to a genetic mutation possessmarkedly elevated plasma HDL-cholesterol levels and apolipoprotein A-l,the major apoprotein component of HDL. In addition, most demonstratemarkedly decreased plasma LDL cholesterol and apolipoprotein B (themajor apolipoprotein component of LDL. (Inazu, A., Brown, M. L., Hesler,C. B., et al.:N. Engl. J. Med. (1990) 323: 1234-1238.)

Given the negative correlation between the levels of HDL cholesterol andHDL associated lipoproteins, and the positive correlation betweentriglycerides, LDL cholesterol, and their associated apolipoproteins inblood with the development of cardiovascular, cerebral vascular andperipheral vascular diseases, the Formula I compounds of this invention,their prodrugs and the salts of such compounds and prodrugs, by virtueof their pharmacologic action, are useful for the prevention, arrestmentand/or regression of atherosclerosis and its associated disease states.These include cardiovascular disorders (e.g., angina, cardiac ischemiaand myocardial infarction), complications due to cardiovascular diseasetherapies (e.g., reperfusion injury and angioplastic restenosis),hypertension, stroke, and atherosclerosis associated with organtransplantation.

Because of the beneficial effects widely associated with elevated HDLlevels, an agent which inhibits CETP activity in humans, by virtue ofits HDL increasing ability, also provides valuable avenues for therapyin a number of other disease areas as well.

Thus, given the ability of the Formula I compounds of this invention,their prodrugs and the salts of such compounds and prodrugs to alterlipoprotein composition via inhibition of cholesterol ester transfer,they are of use in the treatment of vascular complications associatedwith diabetes. Hyperlipidemia is present in most subjects with diabetesmellitus (Howard, B. V. 1987. J. Lipid Res. 28, 613). Even in thepresence of normal lipid levels, diabetic subjects experience a greaterrisk of cardiovascular disease (Kannel, W. B. and McGee, D. L. 1979.Diabetes Care 2, 120). CETP-mediated cholesteryl ester transfer is knownto be abnormally increased in both insulin-dependent (Bagdade, J. D.,Subbaiah, P. V. and Ritter, M. C. 1991. Eur. J. Clin. Invest. 21, 161)and non-insulin dependent diabetes (Bagdade. J. D., Ritter, M. C., Lane,J. and Subbaiah. 1993. Atherosclerosis 104, 69). It has been suggestedthat the abnormal increase in cholesterol transfer results in changes inlipoprotein composition, particularly for VLDL and LDL, that are moreatherogenic (Bagdade, J. D., Wagner, J. D., Rudel, L. L., and Clarkson,T. B. 1995. J. Lipid Res. 36, 759). These changes would not necessarilybe observed during routine lipid screening. Thus the present inventionwill be useful in reducing the risk of vascular complications as aresult of the diabetic condition.

The described agents are useful in the treatment of obesity. In bothhumans (Radeau, T., Lau, P., Robb, M., McDonnell, M., Ailhaud, G. andMcPherson, R., 1995. Journal of Lipid Research. 36 (12):2552-61) andnonhuman primates (Quinet, E., Tall, A., Ramakrishnan, R. and Rudel, L.,1991. Journal of Clinical Investigation. 87 (5):1559-66) mRNA for CETPis expressed at high levels in adipose tissue. The adipose messageincreases with fat feeding (Martin, L. J., Connelly, P. W., Nancoo, D.,Wood, N., Zhang, Z. J., Maguire, G., Quinet, E., Tall, A. R., Marcel, Y.L. and McPherson, R., 1993. Journal of Lipid Research. 34 (3):437-46),and is translated into functional transfer protein and through secretioncontributes significantly to plasma CETP levels. In human adipocytes thebulk of cholesterol is provided by plasma LDL and HDL (Fong, B. S., andAngel, A., 1989.Biochimica et Biophysica Acta. 1004 (1):53-60). Theuptake of HDL cholesteryl ester is dependent in large part on CETP(Benoist, F., Lau, P., McDonnell, M., Doelle, H., Milne, R. andMcPherson, R., 1997. Journal of Biological Chemistry. 272 (38):23572-7).This ability of CETP to stimulate HDL cholesteryl uptake, coupled withthe enhanced binding of HDL to adipocytes in obese subjects (Jimenez, J.G., Fong, B., Julien, P., Despres, J. P., Rotstein, L., and Angel, A.,1989. International Journal of Obesity. 13 (5):699-709), suggests a rolefor CETP, not only in generating the low HDL phenotype for thesesubjects, but in the development of obesity itself by promotingcholesterol accumulation. Inhibitors of CETP activity that block thisprocess therefore serve as useful adjuvants to dietary therapy incausing weight reduction.

CETP inhibitors are useful in the treatment of inflammation due toGram-negative sepsis and septic shock. For example, the systemictoxicity of Gram-negative sepsis is in large part due to endotoxin, alipopolysaccharide (LPS) released from the outer surface of thebacteria, which causes an extensive inflammatory response.Lipopolysaccharide can form complexes with lipoproteins (Ulevitch, R.J., Johnston, A. R., and Weinstein, D. B., 1981. J. Clin. Invest. 67,827-37). In vitro studies have demonstrated that binding of LPS to HDLsubstantially reduces the production and release of mediators ofinflammation (Ulevitch, R. J., Johhston, A. R., 1978. J. Clin. Invest.62, 1313-24). In vivo studies show that transgenic mice expressing humanapo-Al and elevated HDL levels are protected from septic shock (Levine,D. M., Parker, T. S., Donnelly, T. M., Walsh, A. M., and Rubin, A. L.1993. Proc. Natl. Acad. Sci. 90, 12040-44). Importantly, administrationof reconstituted HDL to humans challenged with endotoxin resulted in adecreased inflammatory response (Pajkrt, D., Doran, J. E., Koster, F.,Lerch, P. G., Amet, B., van der Poll, T., ten Cate, J. W., and vanDeventer, S. J. H. 1996. J. Exp. Med. 184, 1601-08). The CETPinhibitors, by virtue of the fact that they raise HDL levels, attenuatethe development of inflammation and septic shock.

The utility of the Formula I compounds of the invention, their prodrugsand the salts of such compounds and prodrugs as medical agents in thetreatment of the above described disease/conditions in mammals (e.g.humans, male or female) is demonstrated by the activity of the compoundsof this invention in conventional assays and the in vivo assay describedbelow. The in vivo assay (with appropriate modifications within theskill in the art) may be used to determine the activity of other lipidor triglyceride controlling agents as well as the compounds of thisinvention. The combination protocol described below is useful fordemonstrating the utility of the combinations of the lipid andtriglyceride agents (e.g., the compounds of this invention) describedherein. Such assays also provide a means whereby the activities of theFormula I compounds of this invention, their prodrugs and the salts ofsuch compounds and prodrugs (or the other agents described herein) canbe compared to each other and with the activities of other knowncompounds. The results of these comparisons are useful for determiningdosage levels in mammals, including humans, for the treatment of suchdiseases.

The following protocols can of course be varied by those skilled in theart.

The hyperalphacholesterolemic activity of the Formula I compounds can bedetermined by assessing the effect of these compounds on the action ofcholesteryl ester transfer protein by measuring the relative transferratio of radiolabeled lipids between lipoprotein fractions, essentiallyas previously described by Morton in J. Biol. Chem. 256, 11992, 1981 andby Dias in Clin. Chem. 34,2322, 1988.

CETP IN VITRO ASSSAY

The following is a brief description of the assay of cholesteryl estertransfer in human plasma (in vitro) and animal plasma (ex vivo): CETPactivity in the presence or absence of drug is assayed by determiningthe transfer of ³H-labeled cholesteryl oleate (CO) from exogenous tracerHDL to the nonHDL lipoprotein fraction in human plasma, or from³H-labeled LDL to the HDL fraction in transgenic mouse plasma. Labeledhuman lipoprotein substrates are prepared similarly to the methoddescribed by Morton in which the endogenous CETP activity in plasma isemployed to transfer ³H-CO from phospholipid liposomes to all thelipoprotein fractions in plasma. ³H-labeled LDL and HDL are subsequentlyisolated by sequential ultracentrifugation at the density cuts of1.019-1.063 and 1.10-1.21 g/ml, respectively. For the activity assay,³H-labeled lipoprotein is added to plasma at 10-25 nmoles CO/ml and thesamples incubated at 37° C. for 2.5-3 hrs. Non-HDL lipoproteins are thenprecipitated by the addition of an equal volume of 20% (wt/vol)polyethylene glycol 8000 (Dias). The samples are centrifuged 750 g×20minutes and the radioactivity contained in the HDL containingsupernatant determined by liquid scintillation. Introducing varyingquantities of the compounds of this invention as a solution indimethylsulfoxide to human plasma, before addition of the radiolabeledcholesteryl oleate, and comparing the relative amounts of radiolabeltransferred allows relative cholesteryl ester transfer inhibitoryactivities to be determined.

CETP IN VIVO ASSSAY

Activity of these compounds in vivo can be determined by the amount ofagent required to be administered, relative to control, to inhibitcholesteryl ester transfer activity by 50% at various time points exvivo or to elevate HDL cholesterol by a given percentage in aCETP-containing animal species. Transgenic mice expressing both humanCETP and human apolipoprotein Al (Charles River, Boston, Mass.) may beused to assess compounds in vivo. The compounds to be examined areadministered by oral gavage in an emulsion vehicle containing olive oiland sodium taurocholate. Blood is taken from mice retroorbitally beforedosing. At various times after dosing, ranging from 4 h to 24 h, theanimals are sacrificed, blood obtained by heart puncture, and lipidparameters measured, including total cholesterol, HDL and LDLcholesterol, and triglycerides. CETP activity is determined by a methodsimilar to that described above except that ³H-cholesteryl oleatecontaining LDL is used as the donor source as opposed to HDL. The valuesobtained for lipids and transfer activity are compared to those obtainedprior to dosing and/or to those from mice receiving vehicle alone.

PLASMA LIPIDS ASSAY

The activity of these compounds may also be demonstrated by determiningthe amount of agent required to alter plasma lipid levels, for exampleHDL cholesterol levels, LDL cholesterol levels, VLDL cholesterol levelsor triglycerides, in the plasma of certain mammals, for examplemarmosets that possess CETP activity and a plasma lipoprotein profilesimilar to that of humans (Crook et al. Arteriosclerosis 10, 625, 1990).Adult marmosets are assigned to treatment groups so that each group hasa similar mean ±SD for total, HDL, and/or LDL plasma cholesterolconcentrations. After group assignment, marmosets are dosed daily withcompound as a dietary admix or by intragastric intubation for from oneto eight days. Control marmosets receive only the dosing vehicle. Plasmatotal, LDL, VLDL and HDL cholesterol values can be determined at anypoint during the study by obtaining blood from an antecubital vein andseparating plasma lipoproteins into their individual subclasses bydensity gradient centrifugation, and by measuring cholesterolconcentration as previously described (Crook et al. Arteriosclerosis 10,625, 1990).

IN VIVO ATHEROSCLEROSIS ASSAY

Anti-atherosclerotic effects of the compounds can be determined by theamount of compound required to reduce the lipid deposition in rabbitaorta. Male New Zealand White rabbits are fed a diet containing 0.2%cholesterol and 10% coconut oil for 4 days (meal-fed once per day).Rabbits are bled from the marginal ear vein and total plasma cholesterolvalues are determined from these samples. The rabbits are then assignedto treatment groups so that each group has a similar mean ±SD for totalplasma cholesterol concentration, HDL cholesterol concentration,triglyceride concentration and/or cholesteryl ester transfer proteinactivity. After group assignment, rabbits are dosed daily with compoundgiven as a dietary admix or on a small piece of gelatin basedconfection. Control rabbits receive only the dosing vehicle, be it thefood or the gelatin confection. The cholesterol/coconut oil diet iscontinued along with the compound administration throughout the study.Plasma cholesterol values and cholesteryl ester transfer proteinactivity can be determined at any point during the study by obtainingblood from the marginal ear vein. After 3-5 months, the rabbits aresacrificed and the aortae are removed from the thoracic arch to thebranch of the iliac arteries. The aortae are cleaned of adventitia,opened longitudinally and then stained with Sudan IV as described byHolman et. al. (Lab. Invest. 1958, 7, 42-47). The percent of the surfacearea stained is quantitated by densitometry using an Optimas ImageAnalyzing System (Image Processing Systems). Reduced lipid deposition isindicated by a reduction in the percent surface area stained in thecompound-receiving group in comparison with the control rabbits.

ANTIOBESITY PROTOCOL

The ability of CETP inhibitors to cause weight loss can be assessed inobese human subjects with body mass index (BMI)≧30 kg/in². Doses ofinhibitor are administered sufficient to result in an increase of≧25% inHDL cholesterol levels. BMI and body fat distribution, defined as waist(W) to hip (H) ratio (WHR), are monitored during the course of the 3-6month studies, and the results for treatment groups compared to thosereceiving placebo.

IN VIVO SEPSIS ASSAY

In vivo studies show that transgenic mice expressing human apo-Al andelevated HDL levels are protected from septic shock. Thus the ability ofCETP inhibitors to protect from septic shock can be demonstrated intransgenic mice expressing both human apo-Al and human CETP transgenes(Levine, D. M., Parker, T. S., Donnelly, T. M., Walsh, A. M. and Rubin,A. L., 1993. Proc. Natl. Acad. Sci. 90, 12040-44). LPS derived from E.coli is administered at 30 mg/kg by i.p. injection to animals which havebeen administered a CETP inhibitor at an appropriate dose to result inelevation of HDL. The number of surviving mice is determined at times upto 48 h after LPS injection and compared to those mice administeredvehicle (minus CETP inhibitor) only.

Administration of the compounds of this invention can be via any methodwhich delivers a compound of this invention systemically and/or locally.These methods include oral routes, parenteral, intraduodenal routes,etc. Generally, the compounds of this invention are administered orally,but parenteral administration (e.g., intravenous, intramuscular,subcutaneous or intramedullary) may be utilized, for example, where oraladministration is inappropriate for the target or where the patient isunable to ingest the drug.

In general an amount of a compound of this invention is used that issufficient to achieve the therapeutic effect desired (e.g., HDLelevation).

In general an effective dosage for the Formula I compounds of thisinvention, their prodrugs and the salts of such compounds and prodrugsis in the range of 0.01 to 10 mg/kg/day, preferably 0.1 to 5 mg/kg/day.

A dosage of the combination pharmaceutical agents to be used inconjuction with the CETP inhibitors is used that is effective for theindication being treated.

For example, typically an effective dosage for HMG-CoA reductaseinhibitors is in the range of 0.01 to 100 mg/kg/day. In general aneffect dosage for the MTP/Apo B secretion inhibitors is in the range of0.01 to 100 mg/kg/day.

The compounds of the present invention are generally administered in theform of a pharmaceutical composition comprising at least one of thecompounds of this invention together with a pharmaceutically acceptablevehicle, diluent or carrier. Thus, the compounds of this invention canbe administered individually or together in any conventional oral,parenteral, rectal or transdermal dosage form.

For oral administration a pharmaceutical composition can take the formof solutions, suspensions, tablets, pills, capsules, powders, and thelike. Tablets containing various excipients such as sodium citrate,calcium carbonate and calcium phosphate are employed along with variousdisintegrants such as starch and preferably potato or tapioca starch andcertain complex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tabletting purposes. Solid compositionsof a similar type are also employed as fillers in soft and hard-filledgelatin capsules; preferred materials in this connection also includelactose or milk sugar as well as high molecular weight polyethyleneglycols. A preferred formulation is a solution or suspension in an oil,for example olive oil, Miglyol™ or Capmul™, in a soft gelatin capsule.Antioxidants may be added to prevent long term degradation asappropriate. When aqueous suspensions and/or elixirs are desired fororal administration, the compounds of this invention can be combinedwith various sweetening agents, flavoring agents, coloring agents,emulsifying agents and/or suspending agents, as well as such diluents aswater, ethanol, propylene glycol, glycerin and various like combinationsthereof.

For purposes of parenteral administration, solutions in sesame or peanutoil or in aqueous propylene glycol can be employed, as well as sterileaqueous solutions of the corresponding water-soluble salts. Such aqueoussolutions may be suitably buffered, if necessary, and the liquid diluentfirst rendered isotonic with sufficient saline or glucose. These aqueoussolutions are especially suitable for intravenous, intramuscular,subcutaneous and intraperitoneal injection purposes. In this connection,the sterile aqueous media employed are all readily obtainable bystandard techniques well-known to those skilled in the art.

For purposes of transdermal (e.g.,topical) administration, dilutesterile, aqueous or partially aqueous solutions (usually in about 0.1%to 5% concentration), otherwise similar to the above parenteralsolutions, are prepared.

Methods of preparing various pharmaceutical compositions with a certainamount of active ingredient are known, or will be apparent in light ofthis disclosure, to those skilled in this art. For examples of methodsof preparing pharmaceutical compositions, see Remington's PharmaceuticalSciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).

Pharmaceutical compositions according to the invention may contain0.1%-95% of the compound(s) of this invention, preferably 1%-70%. In anyevent, the composition or formulation to be administered will contain aquantity of a compound(s) according to the invention in an amounteffective to treat the disease/condition of the subject being treated,e.g., atherosclerosis.

Since the present invention has an aspect that relates to the treatmentof the disease/conditions described herein with a combination of activeingredients which may be administered separately, the invention alsorelates to combining separate pharmaceutical compositions in kit form.The kit comprises two separate pharmaceutical compositions: a compoundof Formula I, a prodrug thereof or a salt of such compound or prodrugsand a second compound as described above. The kit comprises means forcontaining the separate compositions such as a container, a dividedbottle or a divided foil packet. Typically the kit comprises directionsfor the administration of the separate components. The kit form isparticularly advantageous when the separate components are preferablyadministered in different dosage forms (e.g., oral and parenteral), areadministered at different dosage intervals, or when titration of theindividual components of the combination is desired by the prescribingphysician.

An example of such a kit is a so-called blister pack. Blister packs arewell known in the packaging industry and are being widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a preferably transparent plasticmaterial. During the packaging process recesses are formed in theplastic foil. The recesses have the size and shape of the tablets orcapsules to be packed. Next, the tablets or capsules are placed in therecesses and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are sealed in the recesses between the plastic foil and thesheet. Preferably the strength of the sheet is such that the tablets orcapsules can be removed from the blister pack by manually applyingpressure on the recesses whereby an opening is formed in the sheet atthe place of the recess. The tablet or capsule can then be removed viasaid opening.

It may be desirable to provide a memory aid on the kit, e.g., in theform of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be ingested. Another example of such a memory aid is acalendar printed on the card, e.g., as follows “First Week, Monday,Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . ” etc.Other variations of memory aids will be readily apparent. A “daily dose”can be a single tablet or capsule or several pills or capsules to betaken on a given day. Also, a daily dose of Formula I compound canconsist of one tablet or capsule while a daily dose of the secondcompound can consist of several tablets or capsules and vice versa. Thememory aid should reflect this.

In another specific embodiment of the invention, a dispenser designed todispense the daily doses one at a time in the order of their intendeduse is provided. Preferably, the dispenser is equipped with amemory-aid, so as to further facilitate compliance with the regimen. Anexample of such a memory-aid is a mechanical counter which indicates thenumber of daily doses that has been dispensed. Another example of such amemory-aid is a battery-powered micro-chip memory coupled with a liquidcrystal readout, or audible reminder signal which, for example, readsout the date that the last daily dose has been taken and/or reminds onewhen the next dose is to be taken.

The compounds of this invention either alone or in combination with eachother or other compounds generally will be administered in a convenientformulation. The following formulation examples only are illustrativeand are not intended to limit the scope of the present invention.

In the formulations which follow, “active ingredient” means a compoundof this invention.

Formulation 1: Gelatin Capsules Hard gelatin capsules are prepared usingthe following: Ingredient Quantity (mg/capsule) Active ingredient0.25-100  Starch, NF  0-650 Starch flowable powder  0-50 Silicone fluid350 centistokes  0-15 Formulation 2: Tablets A tablet formulation isprepared using the ingredients below: Ingredient Quantity (mg/tablet)Active ingredient 0.25-100  Cellulose, microcrystalline 200-650 Silicondioxide, fumed  10-650 Stearate acid  5-15

The components are blended and compressed to form tablets.

Alternatively, tablets each containing 0.25-100 mg of active ingredientsare made up as follows:

Formulation 3: Tablets Ingredient Quantity (mg/tablet) Active ingredient0.25-100 Starch 45 Cellulose, microcrystalline 35 Polyvinylpyrrolidone(as 10% solution in water) 4 Sodium carboxymethyl cellulose 4.5Magnesium stearate 0.5 Talc 1

The active ingredients, starch, and cellulose are passed through a No.45 mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 50°-60° C. and passed through a No. 18 mesh U.S. sieve. Thesodium carboxymethyl starch, magnesium stearate, and talc, previouslypassed through a No. 60 U.S. sieve, are then added to the granuleswhich, after mixing, are compressed on a tablet machine to yieldtablets.

Suspensions each containing 0.25-100 mg of active ingredient per 5 mldose are made as follows:

Formulation 4: Suspensions Ingredient Quantity (mg/5 ml) Activeingredient 0.25-100 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25mg Benzoic acid solution 0.10 mL Flavor q.v. Color q.v. Purified Waterto 5 mL

The active ingredient is passed through a No. 45 mesh U.S. sieve andmixed with the sodium carboxymethyl cellulose and syrup to form smoothpaste. The benzoic acid solution, flavor, and color are diluted withsome of the water and added, with stirring. Sufficient water is thenadded to produce the required volume.

An aerosol solution is prepared containing the following ingredients:

Formulation 5: Aerosol Ingredient Quantity (% by weight) Activeingredient 0.25 Ethanol 25.75 Propellant 22 (Chlorodifluoromethane)70.00

The active ingredient is mixed with ethanol and the mixture added to aportion of the propellant 22, cooled to 30° C., and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted with the remaining propellant. The valve units arethen fitted to the container.

Suppositories are prepared as follows:

Formulation 6: Suppositories Ingredient Quantity (mg/suppository) ActiveIngredient 250 Saturated fatty acid glycerides 2,000

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimal necessary heat. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

An intravenous formulation is prepared as follows:

Formulation 7: Intravenous Solution Ingredient Quantity Activeingredient dissolved in ethanol 1% 20 mg Intralipid ™ emulsion 1,000 mL

The solution of the above ingredients is intravenously administered to apatient at a rate of about 1 mL per minute.

Soft gelatin capsules are prepared using the following:

Formulation 8: Soft Gelatin Capsule with Oil Formulation IngredientQuantity (mg/capsule) Active Ingredient 10-500 Olive Oil or Miglyol ™Oil 500-1000

The active ingredient above may also be a combination of agents.

GENERAL EXPERIMENTAL PROCEDURES

NMR spectra were recorded on a Varian XL-300 (Varian Co., Palo Alto,Calif.), a Bruker AM-300 spectrometer (Bruker Co., Billerica, Mass.) ora Varian Unity 400 at about 23° C. at 300 MHz for proton and 75.4 mHzfor carbon nuclei. Chemical shifts are expressed in parts per milliondownfield from tetramethylsilane. The peak shapes are denoted asfollows: s, singlet; d, doublet; t, triplet, q, quartet, m, multiplet;bs=broad singlet. Resonances designated as exchangeable did not appearin a separate NMR experiment where the sample was shaken with severaldrops of D₂O in the same solvent. Atmospheric pressure chemicalionization (APCI) mass spectra were obtained on a Fisons Platform IISpectrometer. Chemical ionization mass spectra were obtained on aHewlett-Packard 5989 instrument (Hewlett-Packard Co., Palo Alto, Calif.)(ammonia ionization, PBMS). Where the intensity of chlorine orbromine-containing ions are described, the expected intensity ratio wasobserved (approximately 3:1 for ³⁵Cl/³⁷Cl-containing ions) and 1:1 for⁷⁹Br/⁸¹Br-containing ions) and the intensity of only the lower mass ionis given.

Column chromatography was performed with either Baker Silica Gel (40 μm)(J. T. Baker, Phillipsburg, N.J.) or Silica Gel 60 (EM Sciences,Gibbstown, N.J.) in glass columns under low nitrogen pressure. RadialChromatography was performed using a Chromatron (model 7924T, HarrisonResearch). Unless otherwise specified, reagents were used as obtainedfrom commercial sources. Dimethylformamide, 2-propanol, tetrahydrofuran,and dichloromethane used as reaction solvents were the anhydrous gradesupplied by Aldrich Chemical Company (Milwaukee, Wis.). Microanalyseswere performed by Schwarzkopf Microanalytical Laboratory, Woodside, N.Y.The terms “concentrated” and “evaporated” refer to removal of solvent atwater aspirator pressure on a rotary evaporator with a bath temperatureof less than 45° C. Reactions conducted at “0-20° C.” or “0-25° C.” wereconducted with initial cooling of the vessel in an insulated ice bathwhich was allowed to warm to room temperature over several hours. Theabbreviation “min” and “h” stand for “minutes” and “hours” respectively.

EXAMPLES Example 1

cis-4-Benzyloxycarbonylamino-6,7-dimethoxy-1,2,3,4-tetrahydro-quinoline-2-carboxylicacid butyl ester.

3,4-Dimethoxyaniline (7.5 g, 49.0 mmol), n-butyl glyoxylate (6.5 g, 49.0mmol) and anhydrous sodium sulfate (20 g) were stirred in anhydrousdichloromethane (100 mL) at room temperature. After 90 min, the sodiumsulfate was then filtered off, and to the filtrate was addedO-benzyl-N-vinyl carbamate (5.0 g, 28.2 mmol), followed by borontrifluoride diethyl etherate (1.0 ml). After stirring at roomtemperature for 18 h, the reaction mixture was concentrated and thecrude product was purified by silica gel chromatography using 25% ethylacetate/hexanes as eluent to afford 7.0 g of the title product. ¹H NMR(CDCl₃) δ 0.95 (t, 3H), 1.4 (m, 2H), 1.6 (m, 2H), 2.3 (m, 1H), 2.5 (m,1H), 3.8 (s, 3H), 3.9 (s, 3H), 5.2 (q, 2H), 6.2 (s, 1H), 6.6 (s, 1H),7.4 (m, 5H).

Example 2

cis-4-Benzyloxycarbonylamino-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1,2-dicarboxylicacid 2-butyl ester 1-ethyl ester.

To a solution ofcis-4-benzyloxycarbonylamin-6,7-dimethoxy-1,2,3,4-tetrahydro-quinoline-2-carboxylicacid butyl ester (Example 1) (3.0 g, 6.8 mmol) in anhydrousdichloromethane (100 mL) was added pyridine (1.34 g, 16.9). The mixturewas cooled to 0° C., and ethyl chloroformate (1.47 g, 13.6 mmol) wasslowly added. The reaction was stirred at 0° C. for 30 min, then at roomtemperature for 18 h. The reaction mixture was washed twice with 2N HCland the organic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo. Purification by silica gel chromatography using20% ethyl acetate/hexanes as eluent afforded the title compound (3.1 g).¹H NMR (CDCl₃) δ 0.85 (t, 3H), 1.3 (m, 5H), 1.5 (m, 2H), 3.7 (s, 3H),3.8 (s, 3H), 6.65 (s, 1H), 7.4 (m, 6H).

Example 3

cis-4-Amino-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1,2-dicarboxylic acid2-butyl ester 1-ethyl ester.

cis-4-Benzyloxycarbonylamino-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1,2-dicarboxylicacid 2-butyl ester 1-ethyl ester (Example 2) (800 mg), 10% palladium oncarbon (800 mg), and a mixture of ethanol-cyclohexene (2:1, 60 mL) washeated to 70° C. for 2 h. The reaction mixture was cooled to roomtemperature, filtered through Celite®, and concentrated in vacuo.Purification by silica gel chromatography using to 5% methanoVethylacetate afforded the title compound (500 mg). ¹H NMR (CDCl₃) δ 0.9 (t,3H), 1.4 (m, 5H), 2.5 (m,₁ 1H), 3.9 (d, 6H), 6.9 (s, 1H), 7.2 (s, 1H).

Example 4

cis-4-(3,5-Bis-trifluoromethyl-benzylamino)-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1,2-dicarboxylicacid 2-butyl ester 1-ethyl ester.

To a solution of4-amino-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1,2-dicarboxylic acid2-butyl ester 1-ethyl ester (Example 3) (500 mg, 1.30 mmol) in anhydrousdichloroethane (30 mL) was added acetic acid (79 mg, 1.30 mmol),followed by 3,5-bis(trifluoromethyl)benzaldehyde (318 mg, 1.30 mmol) andsodium triacetoxyborohydride (418 mg, 1.97 mmol). The reaction wasstirred at room temperature for 30 min. The reaction mixture was thendiluted with chloroform and washed with 1N NaOH. The organic layer wasseparated, dried over magnesium sulfate, filtered and concentrated invacuo to afford the crude title compound (approximately 500 mg) whichwas used directly in Example 5.

Example 5

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1,2-dicarboxylicacid 2-butyl ester 1-ethyl ester.

cis-4-(3,5-Bis-trifluoromethyl-benzylamino)-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1,2-dicarboxylicacid 2-butyl ester 1-ethyl ester (Example 4) (approximately 500 mg, 0.83mmol) and pyridine (195 mg, 2.5 mmol) were dissolved in anhydrousdichloromethane (100 mL) and cooled to 0° C. Methyl chloroformate (195mg, 2.1 mmol) was added slowly. The reaction was stirred at 0° C. for 1h, then at room temperature for 18 h. The reaction mixture was thendiluted with chloroform, and washed with 1N HCl. The organic layer wasdried over magnesium sulfate, filtered and concentrated in vacuo.Purification by silica gel chromatography using 15% ethylacetate/hexanes as eluent afforded the title product (400 mg). MS m/z664.2 (M⁺); ¹H NMR (CDCl₃) δ 0.9 (t, 3H), 1.3 (t, 3H), 1.5 (m, 2H), 3.85(s, 3H), 4.0 (t, 2H) 6.3 (s, 1 H), 7.8 (s, 1H).

Example 6

trans-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1,2-dicarboxylicacid 2-butyl ester 1-ethyl ester.

trans-4-Amino-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1,2-dicarboxylicacid 2-butyl ester 1-ethyl ester was isolated as a minor componentduring the preparation of Example 3, and was carried through to desiredproduct as described for Examples 4 and 5. ¹H NMR (CDCl₃) δ 0.9 (t, 3H),1.3 (t, 3H), 3.9 (s, 3H), 4.1 (t, 2H), 6.3 (s, 1H), 7.8 (s, 1H).

Example 7A

Propylidene-(4-trifluoromethyl-phenyl)-amine:

To a solution of 4-trifluoromethylaniline (3.3 g, 20.5 mmol) andtriethylamine (8.3 g, 83 mmol) in 100 mL of dichloromethane, cooled inan ice/water bath, was added slowly titanium tetrachloride (11.4 mL of a1.0M solution in dichloromethane, 11.4 mmol). After 25 min,propionaldehyde (1.8 g, 25.6 mmol) was added slowly as a solution indichloromethane. After an additional hour of stirring in the ice/waterbath, an aqueous potassium carbonate solution was added (˜100 mL of a 1Msolution). The organic phase was separated, dried over magnesiumsulfate, filtered and concentrated in vacuo to afford the crude titleproduct which was used without further purification. ¹H NMR (CDCl₃) δ1.2 (t, 3H), 2.5 (dq, 2H), 7.05 (d, 2H), 7.56 (d, 2H), 7.84 (t, 1H,J=4.4 Hz).

Example 7B

cis-(2-Ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamicacid benzyl ester.

The crude propylidene-(4-trifluoromethyl-phenyl)amine from Example 7Aand O-benzyl-N-vinyl carbamate (3.1 g, 17.4 mmol) were combined in 200mL of dichloromethane, and the mixture was cooled in an ice/water bathas boron trifluoride diethyl etherate (0.25 g, 1.7 mmol) was added.After stirring at room temperature for 1 h, the reaction mixture wasconcentrated to ˜50 mL and directly purified by silica gelchromatography using 50% dichloromethane/hexanes as eluent to afford 2.5g of the title product. ¹H NMR (CDCl₃) δ 0.96 (t, 3H), 1.42 (q, 1H),1.53 (m, 2H), 2.29 (m, 1H), 3.37 (m, 1H), 4.05 (s, 1H), 4.88 (d, 1H),5.00, (m, 1H), 5.16 (s, 2H), 6.44 (d, 1H), 7.20 (dd, 1H), 7.38 (m, 6H).

Example 7C

cis-4-Benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester.

A solution ofcis-(2-ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamicacid benzyl ester (Example 7B) (37.0 g, 97.9 mmol) and pyridine (23.2 g,293.7 mmol) in dichloromethane (1 L) was cooled in an ice/water bath asethyl chloroformate (37.2 g, 342.6 mmol) was added slowly. Afterstirring at room temperature overnight, the mixture was cooled with anice/water bath as a 1M potassium hydroxide solution was added to quenchthe reaction. The organic phase was washed twice with a 2M hydrochloricacid solution, dried over magnesium sulfate, filtered and concentratedin vacuo to afford the crude product which was purified by silica gelchromatography using 10-15% ethyl acetate/hexanes as eluent to afford 40g of the title product. ¹H NMR (CDCl₃) δ 0.83 (t, 3H), 1.28 (t, 3H),1.4-1.6 (m, 3H), 2.53 (m, 1H), 4.23 (m, 2H), 4.47 (m, 1H), 4.80 (m, 1H),4.94 (m, 1H), 5.18 (s, 2H), 7.3-7.6 (m 8H).

Example 7D

cis-4-Amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester:

A solution ofcis-4-benzyloxycarbonylamino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester (Example 7C) (18.0 g, 40 mmol) in 150 mL each ofcyclohexene and ethanol was treated with 10% palladium on carbon (10.0g, 50% water by weight). After heating at reflux for 1 h, the cooledmixture was filtered through Celite® and concentrated in vacuo to affordthe crude product, which was purified by silica gel chromatography using25-50% ethyl acetate/hexanes as eluent to afford 8.8 g of the titleproduct. ¹H NMR (CDCl₃) δ 0.83 (t, 3H), 1.25 (m, 4H), 1.45 (m, 1H), 1.6(m, 1H), 2.49 (m, 1H), 3.81 (m, 1H), 4.2 (m, 2H), 4.4 (m, 1H), 7.47 (m,2H), 7.69 (s, 1H).

Example 7E

cis-4-(3,5-Bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester:

A solution ofcis-4-amino-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester (Example 7D) (8.8 g, 27.8 mmol) was treatedsequentially with acetic acid (5.0 g, 83.5 mmol),3,5-bis-trifluoromethyl-benzaldehyde (6.74 g, 27.8 mmol), followed bysodium triacetoxyborohydride (29.5 g, 139.2 mmol). After stirring atroom temperature for 24 h, the mixture was combined with 500 mL of 1Mpotassium hydroxide, and the aqueous layer was extracted withdichloromethane (2×200 mL). The combined organic phases were dried overmagnesium sulfate, filtered and concentrated in vacuo to afford thecrude product, which was purified by silica gel chromatography using5-10% ethyl acetate/hexanes as eluent to afford 13.8 g of the titleproduct. ¹H NMR (CDCl₃) δ 0.85 (t, 3H), 1.27 (m, 4H), 1.45 (m, 2H), 1.67(m, 1H), 2.66 (m, 1H), 3.56 (m, 1H), 4.1-4.3 (m, 4H), 4.42 (m, 1H), 7.49(d, 1H, J=8.5 Hz), 7.52 (d,1H, J=8.5 Hz), 7.76 (s, 1H), 7.79 (s, 1H),7.91 (s, 2H).

Example 7F

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline1-carboxylicacid ethyl ester:

A solution ofcis-4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester (Example7E) (2.0 g, 3.7 mmol) and pyridine (0.58 g, 7.4mmol) in 100 mL of dichloromethane was cooled in an ice/water bath asmethyl chloroformate (0.87 g, 9.2 mmol) was added slowly. After stirringovernight at room temperature, the reaction mixture was washed twicewith a 2N hydrochloric acid solution, dried over magnesium sulfate,filtered and concentrated in vacuo to afford the crude product, whichwas purified by silica gel chromatography using 5-10% ethylacetate/hexanes as eluent to afford 1.8 g of the title product. MS m/z601 (M⁺+1); ¹H NMR (coalescing mixture of conformers, CDCl₃) δ 0.6-0.8(bm, 3H), 1.2-1.3 (bm, 3H), 1.3-1.5 (bm, 2H), 1.6-1.75 (bm, 1H), 2.1-2.3(bm, 1H), 3.7-3.9 (bs, 3H), 4.04.4 (bm, 4H), 5.0-5.6 (bm, 2H), 7.1 (s,1H), 7.4-7.6 (bm, 2H), 7.6-7.8 (bm, 3H).

Using the appropriate starting materials, Examples 8-91 were prepared inan analogous manner to the sequence of reactions described for Examples1-5 or 7A-7F as appropriate.

Example 8

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethoxy-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester.

MS m/z 628.3 (M⁺), ¹H NMR (CDCl₃) δ 6.85 (s, 1H).

Example 9

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6,7-difluoro-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester.

MS m/z 580.2 (M⁺); ¹H NMR (CDCl₃) δ 3.8 (s, 3H), 6.8 (t, 1H).

Example 10

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid isopropyl ester.

MS m/z 626.5(M⁺); ¹H NMR (CDCl₃) δ 3.75 (s, 3H), 7.1 (s, 1H).

Example 11

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6,7-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 586.3 (M⁺); ¹H NMR (CDCl₃) δ 3.8 (s, 3H), 6.7 (s, 1H).

Example 12

cis4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-pentafluoroethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester.

MS m/z 662.4 (M⁺); ¹H NMR (CDCl₃) δ 3.7 (s, 3H), 7.1 (s, 1H).

Example 13

cis-4-[(3,5-Bis-trifluoromethylbenzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethoxy-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 642.3 (M³⁰ ); ¹H NMR (CDCl₃) δ 3.8 (s, 3H), 6.75 (s, 1H).

Example 14

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-7-trifluoromethoxy-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 642.3 (M⁺); ¹H NMR (CDCl₃) δ 3.8 (s, 3H), 7.0 (m, 1H).

Example 15

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 614.5 (M³⁰ ); 1H NMR (CDCl₃) δ 3.8 (s, 3H), 7.1 (s, 1H).

Example 16

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-propyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 328 (M⁺−300); ¹H NMR (CDCl₃) δ 3.8 (s, 3H), 7.1 (s, 1H).

Example 17

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)methoxycarbonyl-amino]-2-sec-butyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 642.5 (M⁺); ¹H NMR (CDCl₃) δ 3.8 (s, 3H), 7.0 (s, 1H).

Example 18

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-isopropoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 655 (M⁺+1); ¹H NMR (CDCl₃) δ 0.8 (br, 1H), 2.4 (br, 1H), 7.1 (s,1H), 7.1 (s, 1H), 7.7 (s, 1H), 7.8 (s, 1H).

Example 19

cis4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-isobutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 342 (M⁺−300); ¹H NMR (CDCl₃) δ 0.9 (m, 6H), 1.1 (br, 1H), 2.2(br, 1H), 3.8 (s, 3H), 7.1 (s, 1H), 7.5-7.9 (m, 5H).

Example 20

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 629.2 (M⁺+1); ¹H NMR (CDCl₃) δ 0.7 (d, 3H), 3.8 (s, 3H), 7.1 (s,1H), 7.6 (br, 2H), 7.8 (m, 3H).

Example 21

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-isobutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester.

MS m/z 328 (M⁺−300); ¹H NMR (CDCl₃) δ 1.1 (br, 1H), 2.1 (br, 1H), 3.8(s, 3H), 7.1 (s, 1H), 7.6 (br, 2H).

Example 22

cis-4-[(3,5-Bis-trifluoromethylbenzyl)-ethoxycarbonyl-amino]-2-isopropyl-6-trifluoromethyl-3,4dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 643.3 (M³⁰ ); ¹H NMR (CDCl₃) δ 0.7 (d, 3H), 0.8 (d, 3H), 2.1 (br,2H), 7.1 (s, 1H), 7.5 (br, 2H).

Example 23

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-isopropoxycarbonyl-amino]-2-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 656.3 (M³⁰ ); ¹H NMR (CDCl₃) δ 0.7 (d, 3H)₁ 0.8 (d, 3H), 1.2 (d,3H), 1.3 (d, 3H), 7.1 (s, 1H), 7.6 (br, 2H), 7.8 (s, 2H).

Example 24

cis-6-Acetyl-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino-2-cyclopropyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester.

MS m/z 586.4 (M⁺);¹H NMR (CDCl₃) δ 2.6 (s, 3H), 3.8 (s, 3H), 7.5-8.0 (m,6H).

Example 25

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-methoxy-7-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester.

MS m/z 642.5 (M⁺); 1H NMR (CDCl₃) δ 1.3 (t, 3H), 3.8 (s, 6H), 6.5 (s,1H), 7.7 (s, 1H), 7.8 (s, 2H), 7.85 (s, 1H).

Example 26

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-5,6-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester.

MS m/z 572.7 (M⁺); ¹H NMR (CDCl₃) δ 1.3 (t, 3H), 1.7 (d, 3H), 1.8 (d,3H), 3.9 (d, 3H), 4.3 (m, 2H), 6.9 (d, 1H), 7.1 (d, 1H), 7.2 (s, 1H),7.3 (s, 11H), 7.5 (s, 1H).

Example 27

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6,7-dimethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester.

MS m/z 272.7 (M⁺−300); ¹H NMR (CDCl₃) δ 1.3 (t, 3H), 2.3 (d, 6H), 3.8(s, 3H), 6.6 (s, 1H), 7.2 (s, 1H), 7.7 (m, 3H).

Example 28

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-7-trifluoromethoxy-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester.

MS m/z 642.2 (M⁺); ¹H NMR (CDCl₃) δ 3.8 (s, 3H), 7.4 (s, 1H), 7.8 (s,1H).

Example 29

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid 2,2,2-trichloro-1,1-dimethyl-ethyl ester.

MS m/z 743.2 (M⁺); ¹H NMR (CDCl₃) δ 1.9 (s, 3H), 2.0 (s, 3H), 3.8 (s,3H), 7.1(s,1H),7.8 (s, 1H).

Example 30

cis-4-[(3,5-Bis-trifluoromethylbenzyl)-methoxycarbonylamino]-2-cyclopropyl-6-methylsulfanyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 604.5 (M⁺); ¹H NMR (CDCl₃) δ 2.2 (s, 3H), 3.8 (s, 3H), 6.8 (s,1H), 7.1 (d, 1H), 7.4 (s, 1H), 7.7 (m, 3H).

Example 31

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-methanesulfonyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 637.5 (M⁺+1); ¹H NMR (CDCl₃) δ 1.2 (m, 6H), 3.1 (s, 3H), 3.8 (s,3H), 7.5 (s, 1H).

Example 32

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)ethoxycarbonyl-amino]-2-isobutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 642.6 (M⁺+1); ¹H NMR (CDCl₃) δ 0.9 (d, 6H), 1.1 (br, 1H), 7.1 (s,1H), 7.6 (m, 2H), 7.8 (m, 3H).

Example 33

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonylamino]-6-chloro-2-cyclopropyl-7-trifluoromethyl-3,4-dihydro-2H-quinolin-1-carboxylicacid isopropyl ester.

MS m/z 662 (M⁺+2), 679 (M⁺+19); ¹H NMR (CDCl₃) δ 7.03 (s, 1H), 3.81 (s,3H).

Example 34

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)methoxycarbonyl-amino]-6,7-dichloro-2-cyclopropyl-3,4dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 627 (M⁺), 644 (M⁺+17); ¹H NMR (CDCl₃) δ 7.00 (s, 1H), 3.81 (s,3H).

Example 35

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-7-trifluoromethyl-3,4dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 627 (M⁺+1), 644 (M⁺+18); ¹H NMR (CDCl₃) δ 7.40 (d, 1H), 7.06 (d,1H), 3.81 (s, 3H).

Example 36

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)methoxycarbonyl-amino]-7-chloro-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

¹H NMR (CDCl₃) δ 7.18 (s, 1H), 3.81 (s, 3H).

Example 37

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6,7-bis-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 695 (M⁺+1), 712 (M⁺+18); ¹H NMR (CDCl₃) δ 8.01 (s, 1H), 3.83 (s,1H).

Example 38

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-7-fluoro-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 645 (M⁺+1), 662 (M⁺+18); ¹H NMR (CDCl₃) δ 7.81 (s, 1H), 3.81 (s,3H).

Example 39

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-ethoxycarbonyl-amino]-6,7-dimethoxy-2-phenyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester.

MS m/z 654.6 (M³⁰ ); ¹H NMR (CDCl₃) δ 1.1 (t, 3H), 2.4 (m, 1H), 3.8 (s,3H), 3.9 (s, 3H), 6.5 (s, 1H), 7.6 (br, 2H), 7.7 (br, 1H).

Example 40

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-ethoxycarbonylamino]-6,7-dimethoxy-2-(4-trifluoromethyl-phenyl)-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester.

MS m/z 722.6 (M³⁰ ); ¹H NMR (CDCl₃) δ 1.2 (t, 3H), 3.8 (s, 3H), 3.9 (s,3H), 6.5 (s, 1H), 7.3 (d, 2H), 7.5 (d, 2H), 7.7 (br, 2H), 7.8 (br, 1H).

Example 41

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-2-thiophen-2-yl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester.

MS m/z 646 (M⁺); ¹H NMR (CDCl₃) δ 1.2 (t, 3H), 3.8 (s, 3H), 6.4 (s, 1H),6.9 (m, 2H), 7.1 (m, 2H), 7.5 (br, 1H), 7.6 (br, 1H), 7.8 (br, 1H).

Example 42

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-chloro-2-cyclopropyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 594 (M⁺+1), 611 (M⁺+18); ¹H NMR (CDCl₃) δ 6.91 (C5, s, 1H).

Example 43

cis-4-[(4-Bromo-thiophen-2-ylmethyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 576 (M⁺1), 593 (M⁺+18); ¹H NMR (CDCl₃) δ 2.45-2.50 (m, 1H), 3.86(s, 3H).

Example 44

cis-2-Cyclopropyl-4-(methoxycarbonyl-thiophen-2-ylmethyl-amino)-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 496 (MF), 514 (M⁺+18); ¹H NMR (CDCl₃) δ 3.86 (s, 3H), 7.26 (s,1H).

Example 45

cis-2-Cyclopropyl-4-[(3,5-dichloro-benzyl)-methoxycarbonyl-amino]-6-trifluoromethyl-3,4-dihydro-2H-quinoline-carboxylicacid isopropyl ester.

MS m/z 559 (M ), ¹H NMR (CDCl₃) δ 2.40-2.34 (m, 1H), 3.80 (s, 3H).

Example 46

cis-4-(Benzyl-methoxycarbonyl-amino)-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 492 (M⁺+2), 509 (M⁺+19); ¹H NMR (CDCl₃) δ 2.30-2.35 (m, 1H), 3.79(s, 3H).

Example 47

cis-(3,5-Bis-trifluoromethyl-benzyl)-(2-cyclopropyl-1-trifluoroacetyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)carbamicacid methyl ester.

MS m/z 655 (M⁺+19); ¹H NMR (CDCl₃) δ 7.25 (C5,s, 1H).

Example 48

cis-2-Cyclopropyl-4-[(4-isopropenyl-cyclohex-1-enylmethyl)methoxycarbonyl-amino]-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 536 (M⁺+2), 553 (M⁺+19); ¹H NMR (CDCl₃) δ 3.74 (s, 3H), 7.18 (s,1H).

Example 49

cis-4-(Cyclohex-3-enylmethyl-methoxycarbonyl-amino)-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 496 (M⁺+2), 513 (M⁺+19); ¹H NMR (CDCl₃) δ 3.73 (s, 3H), 5.68 (bs,2H).

Example 50

cis-2-Cyclopropyl-4-[(6,6-dimethyl-bicylo[3.1.1]hept-2-en-2-ylmethyl)-methoxycarbonyl-amino]-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 536 (M⁺+2), 553 (M⁺+19); ¹H NMR (CDCl₃) δ 3.74 (s, 3H), 7.16 (s,1H).

Example 51

cis-4-(Bicyclo[2.2.1]hept-5-en-2-ylmethyl-methoxycarbonyl-amino)-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 508 (M⁺+2), 525 (M⁺+19); ¹H NMR (CDCl₃) δ 1.30-1.42 (m, 6H), 3.73(s, 3H).

Example 52

cis-4-[(2-Bromo-3,5-bis-trifluoromethyl-benzyl)methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 706 (M⁺+1), 724 (M⁺+19); ¹H NMR (CDCl₃) δ 3.78 (s, 3H), 7.22 (s,1H).

Example 53

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-(2-ethoxycarbonyl-cyclopropyl)-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 698.6 (M⁺), ¹H NMR (CDCl₃) δ 1.2 (t, 3H), 2.3 (br, 1H), 3.8 (s,3H), 4.1 (q,4H), 7.1 (s, 1H), 7.5 (s, 2H), 7.8 (s, 1H).

Example 54

cis-4-[(2,4-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 628 (M⁺+2), 645 (M⁺+19); ¹H NMR (CDCl₃) δ 3.78 (s, 3H), 7.20 (s,1H).

Example 55

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-7-methyl-6-trifluoromethyl-3,4dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 642 (M⁺+2), 659 (M⁺+19); ¹H NMR (CDCl₃) δ 2.46 (s, 3H), 3.80(3H).

Example 56

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-tert-butyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 643 (M³⁰ ); ¹H NMR (CDCl₃) δ 0.6 (s, 9H), 1.1 (br, 6H), 3.8 (s,3H), 7.1 (s, 1H), 7.5 (br, 1H), 7.7 (s, 1H), 7.8 (s, 2H).

Example 57

cis-4-[(6-Chloro-4-trifluoromethyl-pyridin-2-ylmethyl)methoxycarbonyl-amino]-2-cyclopropyl6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 595 (M⁺+2), 612 (M⁺+19);¹H NMR (CDCl₃) 8 3.78 (s, 3H), 7.15 (s,1H).

Example 58

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclohexyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 669.1 (M⁺+1); ¹H NMR (CDCl₃) δ 3.8 (s, 3H), 7.1 (s, 1H), 7.5 (br,1H), 7.7 (s, 1H), 7.8 (s, 2H).

Example 59

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-ethylsulfanyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 318 (M⁺−300); ¹H NMR (CDCl₃) δ 1.3 (t, 3H), 2.9 (q, 2H), 3.8 (s,3H), 6.9 (s, 1H), 7.4 (s, 1H), 7.6 (s, 1H), 7.7 (s, 1H), 7.8 (s, 1H).

Example 60

cis-2-Cyclopropyl-4-[(4-mercapto-3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 657 (M⁺−1), 658 (M⁺); ¹H NMR (CDCl₃), δ 3.80 (s, 3H), 7.15 (s,1H).

Example 61

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4dihydro-2H-quinoline-1-carboxylicacid isopropenyl ester.

MS m/z 625.5 (M³⁰ ); ¹H NMR (CDCl₃) δ 2.0 (s, 3H), 3.8 (s, 3H), 7.1 (s,1H).

Example 62

cis-4-{[2-(3,5-Bis-trifluoromethyl-phenyl)-ethyl]-methoxycarbonyl-amino}2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 657 (M+NH3)⁺; ¹H NMR (CDCl₃) δ 1.26 (d, 3H), 1.31 (d, 3H), 7.12(s, 1H), 7.50 (d, 1H), 7.59 (d, 1H), 7.65 (s, 2H), 7.76 (s, 1H).

Example 63

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester.

MS m/z 627 (M⁺+1); ¹H NMR (CDCl₃) δ 3.8 (s, 3H), 7.1 (s, 1H), 7.5-7.8(m, 5H).

Example 64

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-2,3,4,6,7,8-hexahydro-cyclopenta[g]quinoline-1-carboxylicacid ethyl ester.

MS m/z 584(M⁺); ¹H NMR (CDCl₃) δ 3.8 (s, 3H), 6.8 (s, 1H), 7.3 (s, 1H).

Example 65

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-ethanesulfinyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

¹H NMR (CDCl₃) δ 2.8 (m, 3H), 4.1 (2H), 3.8 (s, 3H), 7.8 (s, 1H).

Example 66

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)methoxycarbonyl-amino]-2-cyclopropyl-6-ethanesulfonyl-3,4-dihydro2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 651.1 (M³⁰ ); ¹H NMR (CDCl₃) δ 3.7 (s, H), 7.5 (s, 1H).

Example 67

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-2,3,4,6,7,8-hexahydro-cyclopenta[g]quinoline-1-carboxylicacid isopropyl ester.

MS m/z 298.3 (M⁺−300); ¹H NMR (CDCl₃) δ 2.9 (t, 4H), 3.8 (s, 3H), 6.8(s, 1H), 7.6 (s, 1H), 7.7 (s, 1H), 7.8 (s, 1H).

Example 68

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopentyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 655.2 (M³⁰ ); ¹H NMR (CDCl₃) δ 3.8 (s, 3H), 7.1 (s, 1H), 7.5 (br,2H).

Example 69

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclobutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 640.1 (M⁺); ¹H NMR (CDCl₃) δ 3.8 (s, 3H), 7.1 (s, 1H), 7.5 (br,2H).

Example 70

cis-4-[(3,5-Bis-trifluoromethyl-benzylymethoxycarbonyl-amino]-2-cyclopropyl-7-methoxy-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 658 (M⁺+2), 675 (M⁺+19); ¹H NMR (CDCl₃) δ 3.88 (s, 3H), 3.79 (s,3H).

Example 71

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-2,3,4,6,7,8-hexahydrocylopenta[g]quinoline-1-carboxylicacid 1-ethyl-propyl ester.

MS m/z 326.6 (M⁺−300); ¹H NMR (CDCl₃) δ 3.8 (s, 3H), 6.8 (s, 1H), 7.3(s, 1H).

Example 72

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)methoxycarbonyl-amino]-2-cyclopropyl-2,3,4,6,7,8-hexahydro-cyclopenta[g]quinoline-1-carboxylicacid 2,2,2-trifluoro-ethyl ester.

MS m/z 338.1 (M⁺−300); ¹H NMR (CDCl₃) δ 2.9 (m, 4H), 3.8 (s, 3H), 6.8(s, 1H).

Example 73

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-2,3,4,6,7,8-hexahydro-cyclopenta[g]quinoline-1-carboxylicacid dicyclopropylmethyl ester.

MS m/z 350.2 (M⁺−300); ¹H NMR (CDCl₃) δ 3.8 (s, 3H), 6.8 (s, 1H).

Example 74

cis-(3,5-Bis-trifluoromethyl-benzyl)-(2-cyclopropyl-1-trifluoroacetyl-2,3,4,6,7,8-hexahydro-1H-cyclopenta[g]quinolin-4-yl)carbamicacid methyl ester.

¹H NMR (CDCl₃) δ 3.8 (s, 3H), 6.9 (br, 1H), 7.8 (br, 2H).

Example 75

cis-4-[(4-Chloro-3,5-bis-trifluoromethyl-benzyl)methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 660 (M⁺); ¹H NMR (CDCl₃) δ 3.81 (s, 3H), 7.12 (s, 1H).

Example 76

cis-4-[(3,5-Bis-trifluoromethyl-benzylymethoxycarbonyl-amino]-2-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester

¹H NMR (CDCl₃) δ 3.8 (s, 3H), 7.1 (s, 1H), 7.5 (br, 2H).

Example 77

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester.

¹H NMR (CDCl₃) δ 3.8 (s, 3H), 7.1 (s, 1H), 7.5 (br, 2H).

Example 78

cis-4-[(3,5-Bis-trifluoromethyl-benzyl-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester.

MS m/z 613.1 (M⁺); ¹H NMR (CDCl₃) δ 3.8 (s, 3H), 7.1 (s, 1H).

Example 79

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester.

MS m/z 314.1 (M⁺−300); ¹H NMR (CDCl₃) δ 3.8 (s, 3H), 7.1 (s, 1H).

Example 80

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid 2-hydroxy-ethyl ester

¹H NMR (CDCl₃) δ 2.0 (br, 3H), 3.8 (s, 5H), 7.1 (s, 1H), 7.5 (br, 2H).

Example 81

cis[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclobutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester

¹H NMR (CDCl₃) δ 3.8 (s, 3H), 7.1 (s, 1H), 7.5 (s, 2H).

Example 82

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid 2-methoxy-ethyl ester

¹H NMR (CDCl₃) δ 3.3 (m, 4H), 3.6 (m, 4H), 3.8 (s, 3H), 7.1 (s, 1H).

Example 83

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclobutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester

MS m/z 326 (M⁺−300); ¹H NMR (CDCl₃) δ 3.8 (s, 3H), 7.1 (s, 1H), 7.5 (br,2H).

Example 84

cis-4-[(3,5-Bis-trifluoromethyl-benzyl-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid 2-hydroxy-ethyl ester.

MS m/z 316.1 (M⁺−300); ¹H NMR (CDCl₃) δ 3.8 (s, 3H), 7.1 (s, 1H).

Example 85

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclobutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid 2-hydroxy-ethyl ester.

MS m/z 643.1 (M⁺+2); ¹H NMR (CDCl₃) δ 3.8 (m, 5H), 7.1 (s, 1H), 7.5-7.8(m, 5H).

Example 86

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester

¹H NMR (CDCl₃) δ 3.2 (s, 3H), 3.8 (s, 3H), 7.1 (s, 1H).

Example 87

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1carboxylic acid ethyl ester

¹H NMR (CDCl₃) δ 3.1 (s,3H), 3.8 (s, 3H), 7.1 (s, 1H).

Example 88

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester.

MS m/z 630.9 (M³⁰ ) ¹H NMR (CDCl₃) δ 3.2 (s, 3H) , 3.79 (s, 3H).

Example 89

cis-2-Cyclopropyl-4-[methoxycarbonyl-(4-methyl-3,5-bis-trifluoromethyl-benzyl)-amino]-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 640.8 (M⁺); ¹H NMR (CDCl₃) δ 2.55 (s, 3H), 3.79 (s, 3H).

Example 90

cis-4-[(2,6-Bis-trifluoromethyl-biphenyl-4ylmethyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 703 (M⁺+1), 705 (M⁺+3); ¹H NMR (CDCl₃) δ 2.15-2.39 (m, 1H), 3.83(bs, 3H).

Example 91

cis-4-[(3,5-Bis-trifluoromethyl-cyclohexylmethyl)-methoxycarbonyl-amino)-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

MS m/z 633 (M⁺+1); 1H NMR (CDCl₃) δ 3.74 (s, 3H), 7.18 (s, 1H).

Example 92

6,7-Dimethoxy-2-isopropyl-4-oxo-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester.

4,6,7-Trimethoxyquinoline (0.3 g, 1.4 mmol) was dissolved in anhydroustetrahydrofuran (6 mL). The mixture was cooled to −78° C., and isopropylmagnesium chloride (0.8 mL of a 2M solution in tetrahydrofuran, 1.6mmol) was added. The mixture was stirred at −78° C. for 10 min, thenethyl chloroformate (0.16 mL, 1.6 mmol) was added. The reaction waswarmed to room temperature and stirred overnight, then 1N HCl (6 mL) wasadded. After stirring for 1 h, the tetrahydrofuran was removed in vacuo,and the remaining aqueous phase was extracted with ethyl acetate (3×50mL). The organic phases were combined and washed with water (15 mL),dried over sodium sulfate, filtered, and concentrated in vacuo to give0.26 g crude product. Purification by silica gel chromatography using0-40% ethyl acetate/hexanes as eluent afforded the title product (0.23g, 51%). ¹H NMR (CDCl₃) δ 0.85 (d, 3H), 0.9 (d, 3H), 1.33 (t, 3H), 1.8(m, 1H), 2.8 (dd, 1H), 2.93 (dd, 1H), 3.9 (s, 3H), 3.95 (s, 3H), 4.3 (m,2H), 4.5 (m, 1H), 7.3 (bs, 1H), 7.37 (s, 1H).

Examples 93 and 94

cis-4-Benzylamino6,7-dimethoxy-2-isopropyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester andtrans4-Benzylamino-6,7-dimethoxy-2-isopropyl-3,4-dihydro2H-quinoline-1-carboxylicacid ethyl ester,

6,7-Dimethoxy-2-isopropyl-4-oxo-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester (Example 92) (0.254 g, 0.79 mmol) was combined withtriethylamine (0.75 mL, 5.4 mmol) and benzylamine (0.17 mL, 1.6 mmol) inanhydrous dichloromethane (4 mL). This solution was immersed in a roomtemperature water bath, and titanium tetrachloride (0.8 mL of a 1Msolution in dichloromethane, 0.8 mmol) was slowly added. After stirringovernight, a solution of sodium borohydride (0.27 g, 7.2 mmol) inmethanol (6 mL) was carefully added to the mixture. After 3 days, themixture was made basic with 2N KOH and extracted with ethyl acetate(3×50 mL), the combined organic phases were dried over sodium sulfate,filtered, and concentrated in vacuo to afford 0.315 g of material. Thismaterial was purified by silica gel chromatography eluting with 0-30%ethyl acetate in hexanes to afford 35 mg of the title cis product ofExample 93. ¹H NMR (CDCl₃) δ 0.78 (d, 3H), 0.88 (d, 3H), 1.26 (t, 3H),1.35 (m, 1H), 1.9 (m, 1H), 2.43 (ddd, 1H), 3.57 (dd, 1H), 3.85 (s, 3H),3.87 (s, 3H), 3.95 (d, 1H), 4.07 (d, 1H), 4.15 (m, 1H), 4.25 (m, 2H),6.95 (s, 1H), 7.03 (s, 1H), 7.25-7.45 (m, 5H). Further elution of thesilica gel with 40% ethyl acetate in hexanes afforded 130 mg of thetitle trans product of Example 94. ¹H NMR (CDCl₃) δ 0.78 (d, 3H), 0.88(d, 3H), 1.28 (t, 3H), 1.8 (m, 1H), 2.08 (t, 2H), 3.70-3.85 (m, 3H),3.87 (s, 6H), 4.10-4.35 (m, 3H), 6.80 (s, 1H), 7.10 (s, 1H), 7.25-7.45(m, 5H).

Example 95

cis-4-(Benzyl-methoxycarbonyl-amino)-2-isopropyl-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester

To a solution ofcis-4-benzylamino6,7-dimethoxy-2-isopropyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester (Example 93) (22 mg, 0.05 mmol) and pyridine (0.50 mL,6.2 mmol) in anhydrous dichloromethane (1 mL) was added methylchloroformate (0.10 mL, 1.3 mmol) while cooled in an ice bath. Afterstirring at room temperature overnight, water (10 mL), and aqueous 2NKOH (10 mL) were added to the reaction mixture. The solution was stirredfor 30 min, then the mixture was extracted with ethyl acetate (2×10 mL).The organic phases were combined and washed with 1N HCl (2×10 mL), asaturated sodium bicarbonate solution (10 mL), and brine (10 mL). Theorganic layer was dried over sodium sulfate, filtered and concentratedin vacuo to give 88 mg crude product. Purification by silica gelchromatography using 0-40% ethyl acetate/hexanes as eluent afforded thetitle product (12 mg, 50%). MS m/z 471 (M⁺+1), 488 (M⁺+18); ¹H NMR(CDCl₃) δ 0.6-0.8 (m, 6H), 1.25 (t, 3H), 1.4 (m, 1H), 1.8-2.3 (m, 3H),3.8 (s, 6H), 3.85 (s, 3H), 4.0-4.3 (m, 5H), 5.1 (m, 1H), 6.96 (C8, bs,1H), 6.42 (C5, bs, 1H), 7.2-7.4 (m, 5H).

Example 96 was prepared from Example 94 in an analogous manner toExample 95.

Example 96

trans-4-(Benzyl-methoxycarbonyl-amino)-2-isopropyl-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester.

MS m/z 471 (M⁺+1), 488 (M⁺+18). ¹H NMR (CDCl₃) δ 3.86 (C6-OMe, s, 3H),3.77 (C7-OMe, s, 3H).

Examples 97-99 were prepared in an analogous manner to the sequence ofreactions described for Examples 92-95.

Example 97

cis-4-(Benzyl-ethoxycarbonyl-amino)-2-ethyl-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester.

MS m/z 471 (M⁺+1), 488 (M⁺+18); ¹H NMR (CDCl₃) δ 7.00 (C8, s, 1H), 6.42(C5, s, 1H), 0.71 (C2-Et, m, 3H).

Example 98

trans4-(Benzyl-ethoxycarbonyl-amino)-2-ethyl-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1-carboxylicadd ethyl ester.

MS m/z 471 (M⁺+1), 488 (M++18); ¹H NMR (CDCl₃) δ 6.47 (C5, s, 1H), 0.86(C2-Et, t, 3H).

Example 99

cis-2-Allyl-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester.

MS m/z 605 (M⁺+H); ¹H NMR (CDCl₃) δ 7.7 (bs, 1H), 7.5 (bs, 2H), 7.2 (bs,1H), 6.3 (bs, 1H), 3.6 (s, 3H), 1.35 (t, 3H, J=7 Hz).

Example 100A

cis-4-Amino-8-bromo-2-cyclopropyl-6-(trifluoromethyl-1,2,3,4-tetrahydro-quinoline

To a solution ofcis-4-benzyloxycarbonylamino-8-bromo-2-cyclopropyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinoline(1.0 g) (prepared from 2-bromo-4-trifluoromethylaniline andcyclopanecarboxaldehyde as in Example 1) in 20 ml dichloromethane wasadded 30% HBr in HOAc (10 ml) over 5 min, and the resulting mixture wasstirred for 18h. The reaction was quenched with 1M K₂CO₃ solution, thelayers were separated and the aqueous layer was extracted with 50 mLdichloromethane. The combined extracts were dried (MgSO₄), filtered andconcentrated, and the residue was chromatographed (70% EtOActhexane) toafford the title product (500 mg). MS m/z 335.9 (M⁺+1); ¹H NMR (CDCl₃) δ0.3 (m, 2H), 0.6 (m, 2H), 1.0 (m, 1H), 4.0 (m, 1H), 7.5 (s, 1H), 7.6 (s,1H),

Example 100B

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-amino]-8-bromo-2-cyclopropyl-trifluoromethyl-3,4-dihydro-2H-quinoline

To a solution ofcis-amino-8-bromo-2-cyclopropyl-6-trifluoromethyl-1,2,3,4tetrahydro-quinoline(Example 100A) (250 mg, 0.75 mmol) in anhydrous dichloromethane (10 mL)was added acetic acid (112 mg, 1.90 mmol), followed by3,5-bis(trifluoromethyl)benzaldehyde (180 mg, 0.75 mmol) and sodiumtriacetoxyborohydride (791 mg, 3.73 mmol). The reaction was stirred atroom temperature for 5 h. The reaction mixture was then diluted withdichloromethane and washed with 1N NaOH. The organic layer wasseparated, dried over magnesium sulfate, filtered and concentrated invacuo to afford the title crude product (420 mg) which was used withoutfurther purification. ¹H NMR (CDCl₃) δ 0.3 (m, 2H), 0.6 (m, 2H), 1.0 (m,1H), 7.5 (s, 1H), 7.8 (s, 2H), 7.9 (s, 2H).

Example 100C

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-8-bromo-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline

cis-4-[(3,5-bis-trifluoromethyl-benzyl)-amino]-8-bromo-2-cyclopropyl-trifluoromethyl-3,4-dihydro-2H-quinoline(Example 100B) (420 mg, 0.75 mmol) and pyridine (148 mg, 1.88 mmol) weredissolved in anhydrous dichloromethane (15 mL) and cooled to 0° C.Methyl chloroformate (142 mg, 1.5 mmol) was added over 1 min. Thereaction was stirred at 0° C. for 1 h, then at room temperature for 24h. The reaction mixture was then diluted with 50 mL of dichloromethane,and washed twice with 1N HCl. The organic layer was dried over magnesiumsulfate, filtered and concentrated in vacuo to afford the title product(400 mg) which was used without further purification. MS m/z 618.8 (M⁺).

Example 100D

cis4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-8-bromo-2-cyclopropyl-trifluoromethyl-3,4-dihydro2H-quinoline-1-carbonylchloride

A solution ofcis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-8-bromo-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline(Example 100C) (1.0 g) in 50 mL of a 20% phosgene in toluene solutionwas heated to reflux for 24 h. Additional phosgene/toluene (50 ml) wasadded and heating was continued for an additional 24 h. Excess phosgenewas removed by purging with nitrogen. The resulting solution wasconcentrated to afford the crude title product which was used withoutfurther purification. MS m/z 681.5 (M⁺).

Example 101

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-8-bromo-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester

A solution ofcis-4-[(3,5-bis-trifluoromethyl-benzyly)-methoxycarbonyl-amino]-8-bromo-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2Hquinoline-1-carbonyl chloride (Example 100D) (1.5 g) in isopropanol washeated to reflux for 48 h. The reaction was cooled and concentrated, andthe residue was chromatographed (5-10% EtOAc/hexane) to afford the titleproduct (1.0 g). MS m/z 705.4 (M⁺); ¹H NMR (CDCl₃) δ 3.8 (s, 3H), 7.1(s, 1H), 7.8 (s, 2H).

Example 102A

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline

cis-(3,5-Bis-trifluoromethyl-benzyl)-(2-cyclopropyl-1-trifluoroacetyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamicacid methyl ester (Example 47) (900 mg, 1.41 mmol) was dissolved in 20mL of methanol and 60 mL of tetrahydrofuran before adding lithiumhydroxide (1.6 mL of 1.0M aqueous solution, 1.6 mmol) to the solution.After 2 h at room temperature, 100 mL of water was added and the mixtureextracted with ethyl acetate (3×100 mL). The combined organic extractswere washed with 50 mL of brine, dried over sodium sulfate, filtered andconcentrated in vacuo to afford the title product (740 mg) as acolorless solid which was used without further purification. MS m/z 542(M+2)⁺; ¹H NMR (CDCl₃) δ 0.2 (m, 2H), 0.55 (m, 2H), 0.8 (m, 1H).

Example 102B

cis-4-[(3,5-Bis-trifluoromethyl-benzylymethoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carbonylchloride

A solution ofcis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline(Example 102A) (180 mg, 0.33 mmol) in 2 mL of a 1.93M solution ofphosgene in toluene was heated to reflux for 1 h. Excess phosgene wasremoved by purging with nitrogen, and the resulting solution wasconcentrated to afford the crude title product (208 mg) which was usedwithout further purification. MS m/z 621 (M+19⁺); ¹H NMR (CDCl₃) δ 0.2(m, 1H), 0.45 (m, 2H), 0.55 (1H), 0.75 (m, 1H).

Example 102C

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid 2,2,2-trifluoro-ethyl ester.

A solution ofcis-4[(3,5-bis-trifluoromethyl-benzyl)methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4dihydro-2H-quinoline-1-carbonylchloride (Example 102B) (20 mg) in 2,2,2-trifluoroethanol (5 mL) washeated to reflux. After 1 h, the reaction was cooled and concentrated,and the residue was chromatographed (5-10% EtOAc/hexane) to afford thetitle product (22 mg, 77%). MS m/z 685 (M⁺+19); ¹H NMR (CDCl₃) δ 3.82(s, 3H), 7.17 (C5, s, 1H).

Examples 103-106 were prepared using the appropriate alcohol in ananalogous manner to the sequence of reactions used in Examples102A-102C.

Example 103

cis-4[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid cyclopropylmethyl ester.

MS m/z 640 (M+2), 657 (M⁺+19); ¹H NMR (CDCl₃) δ 3.81 (s, 3H), 7.14 (C5,s, 1H).

Example 104

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid butyl ester.

MS m/z 642 (M⁺2), 659 (M⁺+19); ¹H NMR (CDCl₃) δ 3.81 (s, 3H), 7.14 (C5,s, 1H).

Example 105

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid 2,2-dimethyl-propyl ester.

MS m/z 656 (M⁺+2), 673 (M⁺+19); ¹H NMR (CDCl₃), δ 3.81 (s, 3H), 7.14(C5, s, 1H).

Example 106

cis-4-[(3,5-Bis-trifluoromethylbenzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid pentyl ester.

MS m/z 656 (M⁺+2), 673 (M⁺+19); ¹H NMR (CDCl₃) δ 3.81 (s, 3H), 7.14 (C5,s, 1H).

Example 107A

cis-4-(N-Benzyloxycarbonyl-N-tert-butoxycarbonyl)amino-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester.

To a solution ofcis-(2-cyclopropyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamicacid benzyl ester (4.0 9, 10.3 mmol) (prepared from4-trifluoromethylaniline and cyclopropanecarboxaldehyde as in Example 1)in 150 ml anhydrous tetrahydrofuran was added 4-dimethyaminopyridine(5.0 g) and di-tert-butyl dicarbonate (8.96 g, 41 mmol) and theresulting solution was stirred for 24 h. The reaction mixture was pouredinto 100 ml 2N HCl and was extracted 2×200 ml EtOAc. The combinedextracts were dried (MgSO₄), filtered and concentrated to afford thetitle product (6.5 g) which was used without further purification. ¹HNMR (CDCl₃) δ 1.4 (s, 9H), 1.5 (s, 9H), 2.35 (m, 1H), 2.55 (m, 1H), 4.0(q, 1H), 7.3 (s, 5H), 7.5 (m, 3H).

Example 107B

cis-4-tert-Butoxycarbonylamino-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester.

A mixture ofcis-4-(N-benzyloxycarbonyl-N-tert-butoxycarbonyl)amino-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester (Example 107A) (6.5 g) and 10% Pd/C in 50 mL EtOHand 50 ml cyclohexene was refluxed for 1 h. The cooled reaction mixturewas filtered through Celite® and concentrated to afford the titleproduct (3.4 g) which was used without further purification. ¹H NMR(CDCl₃) δ 1.5 (d, 18H), 1.7 (m, 1H), 2.5 (m, 1H), 4.0 (q, 1H), 7.6 (m,3H).

Example 107C

cis-4-Amino-2-cyclopropyl-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester.

Trifluoroacetic acid (3.4 g) was added in portions to a solution ofcis-4-tert-butoxycarbonylamino-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester (Example 107B) (3.4 g; 7.4 mmol) in 150 mldichloromethane, and the reaction was stirred until no starting materialwas observed by thin-layer chromatography. A small amount of 1N NaOH wasadded and the reaction mixture was dried (MgSO₄), filtered andconcentrated. Chromatography on silica gel (50% ethyl acetate:hexanethrough 5% MeOH:dichloromethane) afforded the title product (1.0 g). ¹HNMR (CDCl₃) δ 1.5 (s, 9H), 1.7 (m, 1H), 2.5 (m, 1H), 4.1 (q, 1H), 7.6(m, 3H).

Example 107D

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester.

cis-4-Amino-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester (Example 107C) (1.0g) was subjected to reductiveamination (with 3,5-bis(trifluoromethyl)benzaldehyde as in Example 4 andacylation with methyl chloroformate as in Example 5) to afford 2.4 g ofthe title compound. MS m/z 640 (M⁺); ¹H NMR (CDCl₃) δ 1.5 (s, 9H), 3.8(s, 3H), 7.1 (s, 1H), 7.5-8.0 (m, 4H).

Examples 108-111 were prepared for the appropriate starting materials inan analogous manner to the sequence of reactions described for Examples107A-107D.

Example 108

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethoxy-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester.

MS m/z 657.3 (M⁺); ¹H NMR (CDCl₃) δ 3.8 (s, 3H), 6.8 (t, 1H).

Example 109

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester

MS m/z 529.1 (M⁺−CO2—tBu); ¹H NMR (CDCl₃) δ 0.9 (t, 3H), 1.4 (s, 9H), 8(s, 3H), 7.4 (s, 1H).

Example 110

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester.

¹H NMR (CDCl₃) δ 1.4 (s, 9H), 3.8 (s, 3H), 7.1 (s, 1H), 7.8 (br, 2H).

Example 111

cis-4-(3,5-Bis-trifluoromethyl-benzyl)methoxycarbonyl-amino]-2-cyclopropyl-2,3,4,6,7,8-hexahydro-cyclopenta[g]quinoline-1-carboxylicacid tert-butyl ester

MS m/z 513.2 (M⁺−CO2—tBu); ¹H NMR (CDCl₃) δ 2.1 (t, 21H), 2.9 (m, 4H),3.8 (s, 3H), 6.8 (s, 1H).

Example 112A

(3,5-Bis-trifluoromethylbenzyl)-(7,8-dimethoxy-1-oxo-3,3a,4,5-tetrahydro-2-oxa-9b-aza-cyclopenta[a]naphthalen-5-yl)-carbamicacid methyl ester.

To a solution of cis4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1,2-dicarboxylicacid 2-butyl ester 1-ethyl ester (Example 5) (100 mg, 0.15 mmol) in 8.5mL methanol at 0° C. was added sodium borohydride (57 mg, 1.5 mmol) andthe resulting mixture was stirred at room temperature for 1 h. Thereaction mixture was poured into water and extracted twice with ethylacetate. The combined extracts were dried over magnesium sulfate,filtered and concentrated. The residue was chromatographed using 80%ethyl acetate/hexanes to afford the title product (70 mg). ¹H NMR(CDCl₃) δ 1.8 (br, 1H), 2.4 (br, I H), 3.6 (s, 3H), 6.5 (br, 1H), 7.6(br, 2H), 7.9 (s, 1H).

Example 112B

2-methylsulfanylmethyl-1,2,3,4-tetrahydro-quinolin-4-yl)amine:

To a solution of(3,5-bis-trifluoromethyl-benzyl)-(7,8-dimethoxy-1-oxo-3,3a,4,5-tetrahydro-2-oxa-9b-aza-cyclopenta[a]naphthalen-5-yl)-carbamicacid methyl ester (Example 112A) (700 mg) in dimethyl formamide (15 ml)was added sodium methylthiolate (105 mg, 1.5 mmol) and the resultingsolution was heated to 90° C. for 15 h. The reaction was cooled, waterwas added and the mixture was extracted twice with ethyl acetate. Theextracts were dried (MgSO₄), filtered and concentrated. The residue waschromatographed using 25% ethyl acetate/hexanes to afford the titleproduct (120 mg).

Example 112C

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-ethoxycarbonyl-amino]-6,7-dimethoxy-2-methylsulfanylmethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester.

To an ice-cold solution ofcis-(3,5-bis-trifluoromethyl-benzyl)-(6,7-dimethoxy-2-methylsulfanylmethyl-1,2,3,4-tetrahydro-quinolin-4-yl)amine(Example 112B) (120 mg) and pyridine (0.50 ml) in dichloromethane (30ml) was added ethyl chloroformate (0.5 ml). The solution was stirred at0° C. for 30 min and then at room temperature for 18 h. The reaction wasquenched with water and the mixture was extracted twice with ethylacetate. The combined extracts were dried over magnesium sulfate,filtered and concentrated. The residue was chromatographed with 25%ethyl acetate/hexanes to afford the title product (100 mg). MS m/z 638.3(M⁺); ¹H NMR (CDCl₃) δ 2.1 (s, 3H), 3.8 (s, 3H), 3.9 (s, 3H), 6.4 (s,1H), 7.0 (s, 1H).

Example 113

cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-(2-hydroxymethyl-cyclopropyl)-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

To a solution ofcis-4-(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-(2-ethoxycarbonyl-cyclopropyl)-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester (Example 53) (100 mg, 0.14 mmol) in refluxingmethanol (40 ml) was added sodium borohydride (1.0 g) in portions, andthe resulting mixture was heated to reflux for an additional 30 min. Thecooled reaction was concentrated and the residue was partitioned betweenethyl acetate and 2N HCl. The aqueous layer was extracted again withethyl acetate and the combined extracts were dried (MgSO₄), filtered andconcentrated. The residue was chromatographed with 15-20% ethylacetate/hexane to afford the title product (55 mg). MS m/z 657.2 (M³⁰ );¹H NMR (CDCl₃) δ 3.8 (s, 3H), 3.9 (q, 1H), 7.1 (s, 1H), 7. 5 (s, 2H),7.7 (s, 1H).

Examples 114-122 were prepared in optically enriched form by resolutionof the corresponding racemate indicated, or an intermediate in itssynthesis, using the methods described in the specification.

Example 114

4(S)-[(3,5-Bis-trifluoromethyl-benzylmethoxycarbonyl-amino]-2(S)-isopropl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

Enantiomer of the title product of Example 20.

Example 115

4(S)-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2(S)-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester.

Enantomer of the title product of Example 10.

Example 116

4(S)-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2(S)-cyclopropyl-6-trifluoromethyl-3,4-dihydro2H-quinoline-1-carboxylicacid tert-butyl ester.

Enantiomer of the title product of Example 107D.

Example 117

4(S)-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2(S)-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester.

Enantiomer of the title product of Example 63.

Example 118

4(S)-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2(R)-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicadd isopropyl ester.

Enantiomer of the title product of Example 15.

Example 119

4(S)-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2(S)-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1carboxylicacid ethyl ester.

Enantiomer of the title product of Example 78.

Example 120

4(S)-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2(R)-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester.

Enantiomer of the title product of Example 7F.

Example 121

4(S)-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2(R)-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester.

Enantiomer of the title product of Example 79

Example 122

4(S)-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2(R)-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid 2-hydroxy-ethyl ester.

Enantiomer of Example 84.

What is claimed is:
 1. A compound of the Formula I

a prodrug thereof, or a pharmaceutically acceptable salt of saidcompound or of said prodrug; wherein R¹ is Y, W-X or W-Y; wherein W is acarbonyl, thiocarbonyl, sulfinyl or sulfonyl; X is —O—Y, —S—Y, —N(H)—Yor —N—(Y)₂; wherein Y for each occurrence is independently Z or a fullysaturated, partially unsaturated or fully unsaturated one to tenmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with one or twoheteroatoms selected independently from oxygen, sulfur and nitrogen andsaid carbon is optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with hydroxy, saidcarbon is optionally mono-substituted with oxo, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono-, or di-substituted with oxo, and said carbon chain is optionallymono-substituted with Z; wherein Z is a partially saturated, fullysaturated or fully unsaturated three to eight membered ring optionallyhaving one to four heteroatoms selected independently from oxygen,sulfur and nitrogen, or a bicyclic ring consisting of two fusedpartially saturated, fully saturated or fully unsaturated three to sixmembered rings, taken independently, optionally having one to fourheteroatoms selected independently from nitrogen, sulfur and oxygen;wherein said Z substituent is optionally mono-, di- or tri-substitutedindependently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl, hydroxy,(C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines; R² is a partially saturated, fully saturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one or two heteroatoms selected independently from oxygen,sulfur and nitrogen wherein said carbon atoms are optionally mono-, di-or tri-substituted independently with halo, said carbon is optionallymono-substituted with oxo, said carbon is optionally mono-substitutedwith hydroxy, said sulfur is optionally mono- or di-substituted withoxo, said nitrogen is optionally mono- or di-substituted with oxo; orsaid R² is a partially saturated, fully saturated or fully unsaturatedthree to seven membered ring optionally having one to two heteroatomsselected independently from oxygen, sulfur and nitrogen, wherein said R²ring is optionally attached through (C₁-C₄)alkyl; wherein said R² ringis optionally mono-, di- or tri-substituted independently with halo,(C₂-C₆)alkenyl, (C₁-C₆) alkyl, hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio,amino, nitro, cyano, oxo, carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N-(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-, di- or tri-substituted independently with halo,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, oxo or(C₁-C₆)alkyloxycarbonyl; with the proviso that R¹ is not methyl; R³ ishydrogen or Q; wherein Q is a fully saturated, partially unsaturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V; wherein V is a partially saturated,fully saturated or fully unsaturated three to eight membered ringoptionally having one to four heteroatoms selected independently fromoxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fusedpartially saturated, fully saturated or fully unsaturated three to sixmembered rings, taken independently, optionally having one to fourheteroatoms selected independently from nitrogen, sulfur and oxygen;wherein said V substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxamoyl, mono-N- or di-N,N-(C₁-C₆) alkylcarboxamoyl, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C6)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are also optionallysubstituted with from one to nine fluorines; R⁴ is Q¹ or V¹; wherein Q¹a fully saturated, partially unsaturated or fully unsaturated one to sixmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with oneheteroatom selected from oxygen, sulfur and nitrogen and said carbon isoptionally mono-, di- or tri-substituted independently with halo, saidcarbon is optionally mono-substituted with hydroxy, said carbon isoptionally mono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon chain is optionallymono-substituted with V¹; wherein V¹ is a partially saturated, fullysaturated or fully unsaturated three to six membered ring optionallyhaving one to two heteroatoms selected independently from oxygen, sulfurand nitrogen; wherein said V¹ substituent is optionally mono-, di-,tri-, or tetra-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N-(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituent isalso optionally substituted with from one to nine fluorines; whereineither R³ must contain V or R⁴ must contain V¹; R⁵, R⁶ , R⁷and R⁸ areeach independently hydrogen, a bond, nitro or halo wherein said bond issubstituted with T or a partially saturated, fully saturated or fullyunsaturated (C₁-C₁₂) straight or branched carbon chain wherein carbon,may optionally be replaced with one or two heteroatoms selectedindependently from oxygen, sulfur and nitrogen wherein said carbon atomsare optionally mono-, di- or tri-substituted independently with halo,said carbon is optionally mono-substituted with hydroxy, said carbon isoptionally mono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon is optionally mono-substitutedwith T; wherein T is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen; wherein said Tsubstituent is optionally mono-, di- or tri-substituted independentlywith halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines; and wherein R⁵ and R⁶, or R⁶ and R⁷, and/or R⁷ and R⁸may also be taken together and can form at least one four to eightmembered ring that is partially saturated or fully unsaturatedoptionally having one to three heteroatoms independently selected fromnitrogen, sulfur and oxygen; wherein said ring or rings formed by R⁵ andR⁶, or R⁶ and R⁷, and/or R⁷ and R⁸ are optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines; with the proviso that R¹ is not (C₁-C6)alkyl.
 2. Acompound as recited in claim 1 wherein R² is beta; the C⁴ nitrogen isbeta: R¹ is W-X; W is carbonyl, thiocarbonyl or —SO₂—; X is —O—Y-, S—Y-,N(H)—Y- or —N—(Y)-; Y for each occurrence is independently Z or(C₁-C₄)alkyl, said (C₁-C₄)alkyl optionally substituted with from one tonine fluorines or hydroxy, or said (C₁-C₄)alkyl optionallymono-substituted with Z; wherein Z is a partially saturated, fullysaturated or fully unsaturated three to six membered ring optionallyhaving one to two heteroatoms selected independently from oxygen, sulfurand nitrogen; wherein said Z substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,(C₁-C₄)alkylthio, nitro, cyano, oxo, or (C₁-C₆)alkyloxycarbonyl, said(C₁-C₄)alkyl is optionally substituted with from one to nine fluorines;R² is a partially saturated, fully saturated or fully unsaturated one tofour membered straight or branched carbon chain wherein the carbons,other than the connecting carbon, may optionally be replaced with oneheteroatom selected independently from oxygen, sulfur and nitrogenwherein said carbon atoms are optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withoxo, said carbon is optionally mono-substituted with hydroxy, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo; or said R² is a partiallysaturated, fully saturated or fully unsaturated three to five memberedring optionally having one heteroatom selected independently fromoxygen, sulfur and nitrogen; wherein said R² ring is optionally mono-,di- or tri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxyor (C₁-C₆)alkoxycarbonyl; R³ is Q-V wherein Q is (C₁-C₄)alkyl and V is afive or six membered partially saturated, fully saturated or fullyunsaturated ring optionally having one to three heteroatoms selectedindependently from oxygen, sulfur and nitrogen; wherein said V ring isoptionally mono-, di-, tri- or tetra-substituted independently withhalo, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, nitro, cyano or oxo whereinsaid (C₁-C₆)alkyl substituent optionally has from one to nine fluorines;R⁴ is (C₁-C₄)alkyl; R⁶ and R⁷ are each independently H, halo, T or(C₁-C₆)alkyl, said (C₁-C₆)alkyl optionally having from one to ninefluorines or said (C₁-C₆)alkyl is optionally mono-substituted with T;wherein T is a partially saturated, fully saturated or fully unsaturatedfive to six membered ring optionally having one to two heteroatomsselected independently from oxygen, sulfur and nitrogen; wherein said Tsubstituent is optionally mono-, di- or tri-substituted independentlywith halo, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio,amino, oxo, carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N-(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituentoptionally has from one to nine fluorines; and R⁵ and R⁸ are H, or apharmaceutically acceptable salt thereof.
 3. A compound as recited inclaim 2 wherein W is carbonyl; X is O—Y wherein Y is (C₁-C₄)alkyl, said(C₁-C₄)alkyl substituent optionally substituted with from one to ninefluorines or hydroxy; Q is (C₁-C₄)alkyl and V is phenyl, pyridinyl, orpyrimidinyl; wherein said V ring is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl, hydroxy,(C₁-C₆)alkoxy, nitro, cyano or oxo wherein said (C₁-C₆)alkyl substituentoptionally has from one to nine fluorines; R² is a fully saturated(C₁-C₄) straight or branched carbon chain; or said R is a fullysaturated three to five membered ring; wherein said V chain or ring isoptionally mono-, di- or tri-substituted independently with halo; and R⁶and R⁷ are each independently hydrogen, halo or (C₁-C₆)alkyl, said(C₁-C₆)alkyl optionally having from one to nine fluorines; or apharmaceutically acceptable salt thereof.
 4. A compound as recited inclaim 3 wherein Q is methyl and V is phenyl or pyridinyl; wherein said Vring is optionally mono, di- or tri-substituted independently with halo,(C₁-C₂)alkyl, or nitro wherein said (C₁-C₂)alkyl optionally has from oneto five fluorines, or a pharmaceutically acceptable salt thereof.
 5. Acompound as recited in claim 1 wherein said compound is [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-isopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester; [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-chloro-2-cyclopropyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester; [2S,4S]2-cyclopropyl-4-[(3,5-dichloro-benzyl)-methoxycarbonyl-amino]-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester; [2S,4S]4-[(3,5bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester; [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester; or [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclobutyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester, or a pharmaceutically acceptable salt of saidcompounds.
 6. A compound as recited in claim 1 wherein said compound is[2R,4S]4-[(3,5bis-trifluoromethylbenzylmethoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester; [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester; [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro2H-quinoline-1-carboxylicacid 2-hydroxy-ethyl ester; [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester; [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester; [2S,4S]4[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester; or [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl4-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester, or a pharmaceutically acceptable salt thereof.
 7. Acompound as recited in claim 4 wherein Y is isopropyl; R² is isopropyl;R³ is 3,5-bis-trifluoromethylphenylmethyl; R⁴ is methyl; R⁶ istrifluoromethyl; and R⁷ is H, or a pharmaceutically acceptable saltthereof.
 8. A compound as recited in claim 4 wherein Y is isopropyl; R²is cyclopropyl; R³ is 3,5-bis-trifluoromethylphenylmethyl; R⁴ is methyl;R⁶ is chloro; and R⁷ is H, or a pharmaceutically acceptable saltthereof.
 9. A compound as recited in claim 4 wherein Y is isopropyl; R²is cyclopropyl; R³ is 3,5-dichlorophenylmethyl; R⁴ is methyl; R⁶ istrifluoromethyl; and R⁷ is H, or a pharmaceutically acceptable saltthereof.
 10. A compound as recited in claim 4 wherein Y is tert-butyl;R² is cyclopropyl; R³ is 3,5-bis-trifluoromethylphenylmethyl; R⁴ ismethyl; R⁶ trifluoromethyl; and R⁷ is H, or a pharmaceuticallyacceptable salt thereof.
 11. A compound as recited in claim 4 wherein Yis isopropyl; R² is cyclopropyl; R³ is3,5-bis-trifluoromethylphenylmethyl; R⁴ is methyl; R⁶ trifluoromethyl;and R⁷ is H, or a pharmaceutically acceptable salt thereof.
 12. Acompound as recited in claim 4 wherein Y is isopropyl; R² is cyclobutyl;R³ is 3,5-bis-trifluoromethylphenylmethyl; R⁴ is methyl; R⁶trifluoromethyl; and R⁷ is H, or a pharmaceutically acceptable saltthereof.
 13. A compound as recited in claim 4 wherein Y is isopropyl; R²is ethyl; R³ is 3,5bis-trifluoromethylphenylmethyl; R⁴ is methyl; R⁶ istrifluoromethyl; and R⁷ is H, or a pharmaceutically acceptable saltthereof.
 14. A compound as recited in claim 4 wherein Y is isopropyl; R²is methoxymethyl; R³ is 3,5bis-trifluoromethylphenylmethyl; R⁴ ismethyl; R⁶ is trifluoromethyl; and R⁷ is H, or a pharmaceuticallyacceptable salt thereof.
 15. A compound as recited in claim 4 wherein Yis 2-hydroxyethyl; R² is ethyl; R³ is3,5-bis-trifluoromethylphenylmethyl; R⁴ is methyl; R⁶ istrifluoromethyl; and R⁷ is H, or a pharmaceutically acceptable saltthereof.
 16. A compound as recited in claim 4 wherein Y is ethyl; R² iscyclopropyl; R³ is 3,5-bis-trifluoromethylphenylmethyl; R⁴ is methyl; R⁶is trifluoromethyl; and R⁷ is H, or a pharmaceutically acceptable saltthereof.
 17. A compound as recited in claim 4 wherein Y is ethyl; R² isethyl; R³ is 3,5-bis-trifluoromethylphenylmethyl; R⁴ is methyl; R⁶ istrifluoromethyl; and R⁷ is H, or a pharmaceutically acceptable saltthereof.
 18. A compound as recited in claim 4 wherein Y is n-propyl; R²is cyclopropyl; R³ is 3,5-bis-trifluoromethylphenylmethyl; R⁴ is methyl;R⁶ is trifluoromethyl; and R⁷ is H, or a pharmaceutically acceptablesalt thereof.
 19. A compound as recited in claim 4 wherein Y isn-propyl; R² is ethyl; R³ is 3,5-bis-trifluoromethylphenylmethyl; R⁴ ismethyl; R⁶ is trifluoromethyl; and R⁷ is H, or a pharmaceuticallyacceptable salt thereof.
 20. A compound selected from the groupconsisting of[2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-isopropyl-6-trifluoromethyl-3,4dihydro-2H-quinoline-1-carboxylicacid isopropyl ester; [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-chloro-2-cyclopropyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester; [2S,4S]2-cyclopropyl4-[(3,5-dichlorobenzyl)-methoxycarbonyl-amino]-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester; [2S,4S]4-[(3,5-bis-trifluoromethylbenzyl)-methoxycarbonyl-amino]-2-cyclopropyl--trifluoromethyl-3,4dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester; [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester; [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclobutyl6-trifluoromethyl-3,4-dihydro2H-quinoline-1-carboxylicacid isopropyl ester; [2R,4S]4-[(3,5-bis-trifluoromethyl-benzylmethoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester, [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methoxymethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid isopropyl ester; [2R,4S]4-[(3,5-bis-trifluoromethyl-benzylmethoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4dihydro-2H-quinoline-1-carboxylicacid 2-hydroxy-ethyl ester; [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester; [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl4-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester; [2S,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester; and [2R,4S]4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylicacid propyl ester, or a pharmaceutically acceptable salt thereof.
 21. Acompound as recited in claim 1 wherein R² is beta; the C⁴ nitrogen isbeta; R¹ is W-X; W is carbonyl, thiocarbonyl or sulfonyl; X is —O—Y-,S—Y-, N(H)Y- or —N—(Y)₂-, Y for each occurrence is independently Z or(C₁-C₄)alkyl, said (C₁-C₄)alkyl optionally having from one to ninefluorines or said (C₁-C₄)alkyl optionally mono-substituted with Z;wherein Z is a partially saturated, fully saturated or fully unsaturatedthree to six membered ring optionally having one to two heteroatomsselected independently from oxygen, sulfur and nitrogen; wherein said Zsubstituent is optionally mono, di- or tri-substituted independentlywith halo, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio, nitro, cyano,oxo, or (C₁-C₆)alkyloxycarbonyl, said (C₁-C₄)alkyl substituentoptionally substituted with from one to nine fluorines; R² is apartially saturated, fully saturated or fully unsaturated one to fourmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with oneheteroatom selected independently from oxygen, sulfur and nitrogenwherein said carbon atoms are optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withoxo, said carbon is optionally mono-substituted with hydroxy, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo; or said R² is a partiallysaturated, fully saturated or fully unsaturated three to five memberedring optionally having one heteroatom selected independently fromoxygen, sulfur and nitrogen; wherein said R² ring is optionally mono-,di- or tri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxyor (C₁-C₆)alkoxycarbonyl; R³ is Q-V wherein Q is (C₁-C₄)alkyl and V is afive or six membered partially saturated, fully saturated or fullyunsaturated ring optionally having one to three heteroatoms selectedindependently from oxygen, sulfur and nitrogen; wherein said V ring isoptionally mono-, di-, tri- or tetra-substituted independently withhalo, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, nitro, cyano or oxo whereinsaid (C₁-C₆)alkyl substituent optionally has from one to nine fluorines;R⁴ is (C₁-C₄)alkyl; and R⁵ and R⁶, or R⁶ and R⁷, or R⁷ and R⁸ are takentogether and form one ring that is a partially saturated or fullyunsaturated five or six membered ring optionally having one to twoheteroatoms independently selected from nitrogen, sulfur and oxygen;wherein said ring formed by R⁵ and R⁶, or R⁶ and R⁷, or R⁷ and R⁸ isoptionally mono-, di- or tri-substituted independently with halo,(C₁-C₄)alkyl, (C₁-C₄)alkylsulfonyl, (C₁-C₄)alkenyl, hydroxy,(C,-C₄)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₄)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₄)alkylamino whereinsaid (C₁-C₄)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₄)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₄)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₄)alkylamino or said(C₁-C₄)alkyl substituent optionally has from one to nine fluorines;provided that the R⁵, R⁶, R⁷ and/or R⁸, as the case may be, that do notform the ring are hydrogen, or a pharmaceutically acceptable saltthereof.
 22. A compound as recited in claim 1 wherein R² is beta; the C⁴nitrogen is beta; R¹ is W-Y; W is carbonyl, thiocarbonyl or sulfonyl; Yis (C₁-C₆)alkyl, said (C₁-C₆)alkyl optionally having from one to ninefluorines or said (C₁-C₆)alkyl optionally mono-substituted with Z;wherein Z is a partially saturated, fully saturated or fully unsaturatedthree to six membered ring optionally having one to two heteroatomsselected independently from oxygen, sulfur and nitrogen; wherein said Zsubstituent is optionally mono-, di- or tri-substituted independentlywith halo, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio, nitro, cyano,oxo, or (C₁-C₆)alkyloxycarbonyl, said (C₁-C₄)alkyl optionallysubstituted with from one to nine fluorines; R² is a partiallysaturated, fully saturated or fully unsaturated one to four memberedstraight or branched carbon chain wherein the carbons, other than theconnecting carbon, may optionally be replaced with one heteroatomselected independently from oxygen, sulfur and nitrogen wherein saidcarbon atoms are optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with oxo, saidcarbon is optionally mono-substituted with hydroxy, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono- or di-substituted with oxo; or said R² is a partially saturated,fully saturated or fully unsaturated three to five membered ringoptionally having one heteroatom selected independently from oxygen,sulfur and nitrogen; wherein said R² ring is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy or(C₁-C₆)alkoxycarbonyl; R³ is Q-V wherein Q is (C₁-C₄)alkyl and V is afive or six membered partially saturated, fully saturated or fullyunsaturated ring optionally having one to three heteroatoms selectedindependently from oxygen, sulfur and nitrogen; wherein said V ring isoptionally mono-, di-, tri- or tetra-substituted independently withhalo, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, nitro, cyano or oxo whereinsaid (C₁-C₆)alkyl substituent optionally has from one to nine fluorines;R⁴ is (C₁-C₄)alkyl; R⁶ and R⁷ are each independently (C₁-C₆)alkyl or(C₁-C₈)alkoxy, said (C₁-C₆)alkyl or (C₁-C₆)alkoxy substituentsoptionally having from one to nine fluorines or said (C₁-C₆)alkoxy or(C₁-C₆)alkyl substituents optionally mono-substituted with T; wherein Tis a partially saturated, fully saturated or fully unsaturated five tosix membered ring optionally having one to two heteroatoms selectedindependently from oxygen, sulfur and nitrogen; wherein said Tsubstituent is optionally mono-, di- or tri-substituted independentlywith halo, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio,amino, oxo, carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N-(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituentoptionally has from one to nine fluorines; or R⁶ and R⁷ are takentogether and form one ring that is a partially saturated or fullyunsaturated five or six membered ring optionally having one to twoheteroatoms independently selected from nitrogen, sulfur and oxygen;wherein said ring formed by R⁶ and R⁷ is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₄)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₄)alkenyl, hydroxy, (C₁-C₄)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₄)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₄)alkylamino whereinsaid (C₁-C₄)alkyl substituent optionally has from one to nine fluorines;and R⁵ and R⁸ are H, or a pharmaceutically acceptable salt thereof. 23.A compound as recited in claim 1 wherein R² is beta; the C4 nitrogen isbeta; R¹ is Y; Y is (C₂-C₆)alkenyl or (C₁-C₆)alkyl, said (C₂-C₆)alkenylor (C₁-C₆)alkyl optionally having from one to nine fluorines or said(C₂-C₆)alkenyl or (C₁-C₆)alkyl optionally mono-substituted with Z;wherein Z is a partially saturated, fully saturated or fully unsaturatedthree to six membered ring optionally having one to two heteroatomsselected independently from oxygen, sulfur and nitrogen; wherein said Zsubstituent is optionally mono-, di- or tri-substituted independentlywith halo, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio, nitro, cyano,oxo, or (C₁-C₆)alkyloxycarbonyl, said (C₁-C₄)alkyl substituentoptionally substituted with from one to nine fluorines; R² is apartially saturated, fully saturated or fully unsaturated one to fourmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with oneheteroatom selected independently from oxygen, sulfur and nitrogenwherein said carbon atoms are optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withoxo, said carbon is optionally mono-substituted with hydroxy, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo; or said R² is a partiallysaturated, fully saturated or fully unsaturated three to five memberedring optionally having one heteroatom selected independently fromoxygen, sulfur and nitrogen; wherein said R² ring is optionally mono-,di- or tri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxyor (C₁-C₆)alkoxycarbonyl; R³ is Q-V wherein Q is (C₁-C₄)alkyl and V is afive or six membered partially saturated, fully saturated or fullyunsaturated ring optionally having one to three heteroatoms selectedindependently from oxygen, sulfur and nitrogen; wherein said V ring isoptionally mono-, di-, tri- or tetra-substituted independently withhalo, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, nitro, cyano or oxo whereinsaid (C₁-C₆)alkyl substituent optionally has from one to nine fluorines;R⁴ is (C₁-C₄)alkyl; R⁶ and R⁷ are each independently (C₁-C₆)alkyl or(C,-C₆)alkoxy, said (C₁-C₆)alkyl or (C₁-C₆)alkoxy substituentsoptionally having from one to nine fluorines or said (C₁-C₆)alkoxy or(C₁-C₆)alkyl substituents optionally mono-substituted with T, wherein Tis a partially saturated, fully saturated or fully unsaturated five tosix membered ring optionally having one to two heteroatoms selectedindependently from oxygen, sulfur and nitrogen; wherein said Tsubstituent is optionally mono-, di- or tri-substituted independentlywith halo, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio,amino, oxo, carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N-(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituentoptionally has from one to nine fluorines; or R⁶ and R⁷ are takentogether and form one ring that is a partially saturated or fullyunsaturated five or six membered ring optionally having one to twoheteroatoms independently selected from nitrogen, sulfur and oxygen;wherein said ring formed by R⁵ and R⁷ is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₄)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₄)alkenyl, hydroxy, (C₁-C₄)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₄)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₄)alkylamino whereinsaid (C₁-C₄)alkyl substituent optionally has from one to nine fluorines;and R⁵ and R⁸ are H, or a pharmaceutically acceptable salt thereof. 24.A compound as recited in claim 1 wherein R² is beta; the C⁴ nitrogen isbeta; R¹ is Z; Z is a partially saturated, fully saturated or fullyunsaturated three to six membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen;wherein said Z substituent is optionally mono-, di- or tri-substitutedindependently with halo, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio,nitro, cyano, oxo, or (C₁-C₆)alkyloxycarbonyl, said (C₁-C₄)alkylsubstituent optionally having one to nine fluorines; R² is a partiallysaturated, fully saturated or fully unsaturated one to four memberedstraight or branched carbon chain wherein the carbons, other than theconnecting carbon, may optionally be replaced with one heteroatomselected independently from oxygen, sulfur and nitrogen wherein saidcarbon atoms are optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with oxo, saidcarbon is optionally mono-substituted with hydroxy, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono- or di-substituted with oxo; or said R is a partially saturated,fully saturated or fully unsaturated three to five membered ringoptionally having one heteroatom selected independently from oxygen,sulfur and nitrogen; wherein said R² ring is optionally mono, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy or(C₁-C₆)alkoxycarbonyl; R³ is Q-V wherein Q is (C₁-C₄)alkyl and V is afive or six membered partially saturated, fully saturated or fullyunsaturated ring optionally having one to three heteroatoms selectedindependently from oxygen, sulfur and nitrogen; wherein said V ring isoptionally mono-, di-, tri- or tetra-substituted independently withhalo, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, nitro, cyano or oxo whereinsaid (C₁-C₆)alkyl substituent optionally has from one to nine fluorines;R⁴ is (C₁-C₄)alkyl; R⁶ and R⁷ are each independently (C₁-C₆)alkyl or(C₁-C₆)alkoxy, said (C₁-C₆)alkyl or (C₁-C₆)alkoxy substituentsoptionally having from one to nine fluorines or said (C₁-C₆)alkoxy or(C₁-C₆)alkyl substituents optionally mono-substituted with T; wherein Tis a partially saturated, fully saturated or fully unsaturated five tosix membered ring optionally having one to two heteroatoms selectedindependently from oxygen, sulfur and nitrogen; wherein said Tsubstituent is optionally mono-, di- or tri-substituted independentlywith halo, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio,amino, oxo, carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N-(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituentoptionally has from one to nine fluorines; or R⁶ and R⁷ are takentogether and form one ring that is a partially saturated or fullyunsaturated five or six membered ring optionally having one to twoheteroatoms independently selected from nitrogen, sulfur and oxygen;wherein said ring formed by R⁶ and R⁷ is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₄)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₄)alkenyl, hydroxy, (C₁-₄)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₄)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₄)alkylamino whereinsaid (C₁-C₄)alkyl substituent optionally has from one to nine fluorines;and R⁵ and R⁸ are H, or a pharmaceutically acceptable salt thereof. 25.A compound as recited in claim 1 wherein R² is beta; the C⁴ nitrogen isbeta: R¹ is W-Z; W is carbonyl, thiocarbonyl or sulfonyl; Z is apartially saturated, fully saturated or fully unsaturated three to sixmembered ring optionally having one to two heteroatoms selectedindependently from oxygen, sulfur and nitrogen; wherein said Zsubstituent is optionally mono-, di- or tri-substituted independentlywith halo, (C₁-C₆)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio, nitro, cyano,oxo, or (C₁-C₆)alkyloxycarbonyl, said (C₁-C₄)alkyl substituentoptionally having from one to nine fluorines; R² is a partiallysaturated, fully saturated or fully unsaturated one to four memberedstraight or branched carbon chain wherein the carbons, other than theconnecting carbon, may optionally be replaced with one heteroatomselected independently from oxygen, sulfur and nitrogen wherein saidcarbon atoms are optionally mono-, di- or tri-substituted independentlywith halo, said carbon is optionally mono-substituted with oxo, saidcarbon is optionally mono-substituted with hydroxy, said sulfur isoptionally mono- or di-substituted with oxo, said nitrogen is optionallymono- or di-substituted with oxo; or said R² is a partially saturated,fully saturated or fully unsaturated three to five membered ringoptionally having one heteroatom selected independently from oxygen,sulfur and nitrogen; wherein said R² ring is optionally mono, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy or(C₁-C₆)alkoxycarbonyl; R³ is Q-V wherein Q is (C₁-C₄)alkyl and V is afive or six membered partially saturated, fully saturated or fullyunsaturated ring optionally having one to three heteroatoms selectedindependently from oxygen, sulfur and nitrogen; wherein said V ring isoptionally mono-, di-, tri- or tetra-substituted independently withhalo, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, nitro, cyano or oxo whereinsaid (C₁-C₆)alkyl substituent optionally has from one to nine fluorines;R⁴ is (C₁-C₄)alkyl; R⁶ and R⁷ are each independently (C₁-C₆)alkyl or(C₁-C,)alkoxy, said (C₁-C₆)alkyl or (C₁-C₆)alkoxy substituentsoptionally having from one to nine fluorines or said (C₁-C₆)alkoxy or(C₁-C₆)alkyl substituents optionally mono-substituted with T; wherein Tis a partially saturated, fully saturated or fully unsaturated five tosix membered ring optionally having one to two heteroatoms selectedindependently from oxygen, sulfur and nitrogen; wherein said Tsubstituent is optionally mono-, di- or tri-substituted independentlywith halo, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio,amino, oxo, carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N-(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituentoptionally has from one to nine fluorines; or R⁶ and R⁷ are takentogether and form one ring that is a partially saturated or fullyunsaturated five or six membered ring optionally having one to twoheteroatoms independently selected from nitrogen, sulfur and oxygen;wherein said ring formed by R⁶ and R⁷ is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₄)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₄)alkenyl, hydroxy, (C₁-C₄)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₄)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₄)alkylamino whereinsaid (C₁-C₄)alkyl substituent optionally has from one to nine fluorines;and R⁵ and R⁸ are H, or a pharmaceutically acceptable salt thereof. 26.A compound as recited in claim 1 wherein R² is beta; the C⁴ nitrogen isbeta; R¹ is W-X; W is carbonyl, thiocarbonyl or sulfonyl; X is —O—Y-,S—Y-, N(H)—Y- or —N—(Y-; Y for each occurrence is independently Z or(C₁-C₆)alkyl, said (C₁-C₄)alkyl substituent optionally having from oneto nine fluorines or said (C₁-C₄)alkyl optionally mono-substituted withZ wherein Z is a partially saturated, fully saturated or fullyunsaturated three to six membered ring optionally having one to twoheteroatoms selected independently from oxygen, sulfur and nitrogen;wherein said Z substituent is optionally mono-, di- or tri-substitutedindependently with halo, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio,nitro, cyano, oxo, or (C₁-C₆)alkyloxycarbonyl, said (C₁-C₄)alkylsubstituent optionally substituted with from one to nine fluorines; R²is a partially saturated, fully saturated or fully unsaturated one tofour membered straight or branched carbon chain wherein the carbons,other than the connecting carbon, may optionally be replaced with oneheteroatom selected independently from oxygen, sulfur and nitrogenwherein said carbon atoms are optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withoxo, said carbon is optionally mono-substituted with hydroxy, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo; or said R² is a partiallysaturated, fully saturated or fully unsaturated three to five memberedring optionally having one heteroatom selected independently fromoxygen, sulfur and nitrogen; wherein said R² ring is optionally mono-,di- or tri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxyor (C₁-C₆)alkoxycarbonyl; R³ is Q-V wherein Q is (C₁-C₄)alkyl and V is afive or six membered partially saturated, fully saturated or fullyunsaturated ring optionally having one to three heteroatoms selectedindependently from oxygen, sulfur and nitrogen; wherein said V ring isoptionally mono-, di-, tri- or tetra-substituted independently withhalo, (C₁-C₆)alkyl, hydroxy, (C₁-C₆)alkoxy, nitro, cyano or oxo whereinsaid (C₁-C₆)alkyl substituent optionally has from one to nine fluorines;R⁴ is (C₁-C₄)alkyl; at least one of R⁶ and R⁷ is (C₁-C₄)alkoxy and atleast one of R⁶ and R⁷ is (C₁-C₆)alkyl, said (C₁-C₆)alkyl and(C₁-C₄)alkoxy substituents optionally having from one to nine fluorinesor said (C₁-C₆)alkyl and (C₁-C₄)alkoxy substituents optionallymono-substituted with T, wherein T is a partially saturated, fullysaturated or fully unsaturated five to six membered ring optionallyhaving one to two heteroatoms selected independently from oxygen, sulfurand nitrogen; wherein said T substituent is optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl, hydroxy,(C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent optionally has from one to nine fluorines;and R⁵ and R⁸ are H, or a pharmaceutically acceptable salt thereof. 27.A method for treating atherosclerosis, peripheral vascular disease,dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia,hypercholesterolemia, hypertriglyceridemia,familial-hypercholesterolemia, cardiovascular disorders, angina,ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusioninjury, angioplastic restenosis, hypertension, vascular complications ofdiabetes, obesity or endotoxemia in a mammal by administering to amammal in need of such treatment an atherosclerosis, peripheral vasculardisease, dyslipidemia, hyperbetalipoproteinemia,hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia,familial-hypercholesterolemia, cardiovascular disorders, angina,ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusioninjury, angioplastic restenosis, hypertension, reperfusion injury,vascular complications of diabetes, obesity or endotoxemia treatingamount of a compound of claim 1, a prodrug thereof, or apharmaceutically acceptable salt of said compound or of said prodrug.28. A method as recited in claim 27 wherein atherosclerosis is treated.29. A method as recited in claim 27 wherein peripheral vascular diseaseis treated.
 30. A method as recited in claim 27 wherein dyslipidemia istreated.
 31. A method as recited in claim 27 whereinhyperbetalipoproteinemia is treated.
 32. A method as recited in claim 27wherein hypoalphalipoproteinemia is treated.
 33. A method as recited inclaim 27 wherein hypercholesterolemia is treated.
 34. A method asrecited in claim 27 wherein hypertriglyceridemia is treated.
 35. Amethod as recited in claim 27 wherein cardiovascular disorders aretreated.
 36. A pharmaceutical composition which comprises atherapeutically effective amount of a compound of claim 1, a prodrugthereof, or a pharmaceutically acceptable salt of said compound or ofsaid prodrug and a pharmaceutically acceptable carrier.
 37. Apharmaceutical composition for the treatment of atherosclerosis,peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia,hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia,familial-hypercholesterolemia, cardiovascular disorders, angina,ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusioninjury, angioplastic restenosis, hypertension, vascular complications ofdiabetes, obesity or endotoxemia in a mammal which comprise atherapeutically effective amount of a compound of claim 1, a prodrugthereof, or a pharmaceutically acceptable salt of said compound or ofsaid prodrug and a pharmaceutically acceptable carrier.
 38. Apharmaceutical composition for the treatment of atherosclerosis in amammal which comprises an atherosclerosis treating amount of a compoundof claim 1, a prodrug thereof, or a pharmaceutically acceptable salt ofsaid compound or of said prodrug and a pharmaceutically acceptablecarrier.
 39. A method for treating atherosclerosis, peripheral vasculardisease, dyslipidemia, hyperbetalipoproteinemia,hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia,familial-hypercholesterolemia, angina, reperfusion injury, angioplasticrestenosis, hypertension, vascular complications of diabetes, obesity orendotoxemia in a mammal by administering to a mammal in need of suchtreatment an atherosclerosis, peripheral vascular disease, dyslipidemia,hyperbetalipoproteinemia, hypoalphalipoproteinemia,hypercholesterolemia, hypertriglyceridemia,familial-hypercholesterolemia, angina, reperfusion injury, angioplasticrestenosis, hypertension, reperfusion injury, vascular complications ofdiabetes, obesity or endotoxemia treating amount of a compound of theFormula I

a prodrug thereof, or a pharmaceutically acceptable salt of saidcompound or of said prodrug; wherein R¹ is hydrogen, Y, W-X or W-Y;wherein W is a carbonyl, thiocarbonyl, sulfinyl or sulfonyl; X is —O—Y,—S—Y, —N(H)—Y or —N—(Y)₂; wherein Y for each occurrence is independentlyZ or a fully saturated, partially unsaturated or fully unsaturated oneto ten membered straight or branched carbon chain wherein the carbons,other than the connecting carbon, may optionally be replaced with one ortwo heteroatoms selected independently from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono-, or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with Z; wherein Z is a partially saturated,fully saturated or fully unsaturated three to eight membered ringoptionally having one to four heteroatoms selected independently fromoxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fusedpartially saturated, fully saturated or fully unsaturated three to sixmembered rings, taken independently, optionally having one to fourheteroatoms selected independently from nitrogen, sulfur and oxygen;wherein said Z substituent is optionally mono-, di- or tri-substitutedindependently with halo, (C₂-C₆)alkenyl, (C₁-C₆) alkyl, hydroxy,(C₁-C₆)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with halo, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines; R² is a partially saturated, fully saturated or fullyunsaturated one to six membered straight or branched carbon chainwherein the carbons, other than the connecting carbon, may optionally bereplaced with one or two heteroatoms selected independently from oxygen,sulfur and nitrogen wherein said carbon atoms are optionally mono-, di-or tri-substituted independently with halo, said carbon is optionallymono-substituted with oxo, said carbon is optionally mono-substitutedwith hydroxy, said sulfur is optionally mono- or di-substituted withoxo, said nitrogen is optionally mono- or di-substituted with oxo; orsaid R² is a partially saturated, fully saturated or fully unsaturatedthree to seven membered ring optionally having one to two heteroatomsselected independently from oxygen, sulfur and nitrogen, wherein said R²ring is optionally attached through (C₁-C₄)alkyl; wherein said R² ringis optionally mono-, di- or tri-substituted independently with halo,(C₂-C₆)alkenyl, (C₁-C₆) alkyl, hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio,amino, nitro, cyano, oxo, carboxy, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N-(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-, di- or tri-substituted independently with halo,hydroxy, (C₁-C₆)alkoxy, (C₁-C₄)alkylthio, oxo or(C₁-C₆)alkyloxycarbonyl; with the proviso that R¹ is not methyl; R³ ishydrogen or Q; wherein Q is a fully saturated, partially unsaturated orfully unsaturated one to six membered straight or branched carbon chainwherein the carbons other than the connecting carbon, may optionally bereplaced with one heteroatom selected from oxygen, sulfur and nitrogenand said carbon is optionally mono-, di- or tri-substitutedindependently with halo, said carbon is optionally mono-substituted withhydroxy, said carbon is optionally mono-substituted with oxo, saidsulfur is optionally mono- or di-substituted with oxo, said nitrogen isoptionally mono- or di-substituted with oxo, and said carbon chain isoptionally mono-substituted with V; wherein V is a partially saturated,fully saturated or fully unsaturated three to eight membered ringoptionally having one to four heteroatoms selected independently fromoxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fusedpartially saturated, fully saturated or fully unsaturated three to sixmembered rings, taken independently, optionally having one to fourheteroatoms selected independently from nitrogen, sulfur and oxygen;wherein said V substituent is optionally mono-, di-, tri-, ortetra-substituted independently with halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl,hydroxy, (C₁-C6)alkoxy, (C₁-C₄)alkylthio, amino, nitro, cyano, oxo,carboxamoyl, mono-N- or di-N,N-(C₁-C₆) alkylcarboxamoyl, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl or (C₂-C₆)alkenyl substituent is optionally mono-, di-or tri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl or (C₂-C₆)alkenyl substituents are also optionallysubstituted with from one to nine fluorines; R⁴ is Q¹ or V¹; wherein Q¹a fully saturated, partially unsaturated or fully unsaturated one to sixmembered straight or branched carbon chain wherein the carbons, otherthan the connecting carbon, may optionally be replaced with oneheteroatom selected from oxygen, sulfur and nitrogen and said carbon isoptionally mono-, di- or tri-substituted independently with halo, saidcarbon is optionally mono-substituted with hydroxy, said carbon isoptionally mono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon chain is optionallymono-substituted with V¹; wherein V¹ is a partially saturated, fullysaturated or fully unsaturated three to six membered ring optionallyhaving one to two heteroatoms selected independently from oxygen, sulfurand nitrogen; wherein said V¹ substituent is optionally mono-, di-,tri-, or tetra-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, amino, nitro, cyano, (C₁-C₆)alkyloxycarbonyl, mono-N- ordi-N,N-(C₁-C₆)alkylamino wherein said (C₁-C₆)alkyl substituent isoptionally mono-substituted with oxo, said (C₁-C₆)alkyl substituent isalso optionally substituted with from one to nine fluorines; whereineither R³ must contain V or R⁴ must contain V¹; R⁵ , R⁶, R⁷ and R⁸ areeach independently hydrogen, a bond, nitro or halo wherein said bond issubstituted with T or a partially saturated, fully saturated or fullyunsaturated (C₁-C₁₂) straight or branched carbon chain wherein carbon,may optionally be replaced with one or two heteroatoms selectedindependently from oxygen, sulfur and nitrogen wherein said carbon atomsare optionally mono-, di- or tri-substituted independently with halo,said carbon is optionally mono-substituted with hydroxy, said carbon isoptionally mono-substituted with oxo, said sulfur is optionally mono- ordi-substituted with oxo, said nitrogen is optionally mono- ordi-substituted with oxo, and said carbon is optionally mono-substitutedwith T; wherein T is a partially saturated, fully saturated or fullyunsaturated three to eight membered ring optionally having one to fourheteroatoms selected independently from oxygen, sulfur and nitrogen, or,a bicyclic ring consisting of two fused partially saturated, fullysaturated or fully unsaturated three to six membered rings, takenindependently, optionally having one to four heteroatoms selectedindependently from nitrogen, sulfur and oxygen; wherein said Tsubstituent is optionally mono-, di- or tri-substituted independentlywith halo, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines; and wherein R⁵ and R⁶, or R⁶ and R⁷, and/or R⁷ and R⁸may also be taken together and can form at least one four to eightmembered ring that is partially saturated or fully unsaturatedoptionally having one to three heteroatoms independently selected fromnitrogen, sulfur and oxygen; wherein said ring or rings formed by R⁵ andR⁶, or R⁶ and R⁷, and/or R⁷ and R⁸ are optionally mono-, di- ortri-substituted independently with halo, (C₁-C₆)alkyl,(C₁-C₄)alkylsulfonyl, (C₂-C₆)alkenyl, hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino whereinsaid (C₁-C₆)alkyl substituent is optionally mono-, di- ortri-substituted independently with hydroxy, (C₁-C₆)alkoxy,(C₁-C₄)alkylthio, amino, nitro, cyano, oxo, carboxy,(C₁-C₆)alkyloxycarbonyl, mono-N- or di-N,N-(C₁-C₆)alkylamino, said(C₁-C₆)alkyl substituent is also optionally substituted with from one tonine fluorines; with the proviso that when R² is carboxyl or(C₁-C₄)alkylcarboxyl, then R¹ is not hydrogen.
 40. A method as recitedin claim 39 wherein atherosclerosis is treated with an atherosclerosistreating amount of a Formula I compound or a pharmaceutically acceptablesalt of said compound.
 41. A method as recited in claim 39 whereindyslipidemia is treated with a dyslipidemia treating amount of a FormulaI compound or a pharmaceutically acceptable salt of said compound.
 42. Amethod as recited in claim 39 wherein hyperbetalipoproteinemia istreated with a hyperbetalipoproteinemia treating amount of a Formula Icompound or a pharmaceutically acceptable salt of said compound.
 43. Amethod as recited in claim 39 wherein hypoalphalipoproteinemia istreated with a hypoalphalipoproteinemia treating amount of a Formula Icompound or a pharmaceutically acceptable salt of said compound.
 44. Amethod as recited in claim 39 wherein hypercholesterolemia is treatedwith a hypercholesterolemia treating amount of a Formula I compound or apharmaceutically acceptable salt of said compound. 45.cis-(2-Ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamicacid benzyl ester.